Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:16]2[N:24]=[C:4]([OH:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Yield: 64 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([CH:64]([CH3:66])[CH3:65])[C:8]([NH:10][C@@H:11]([CH3:63])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH:23]3[CH:29]=[N:28][C:27]4[CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]5[C:42]([O:59][CH3:60])=[CH:43][C:44]6[C:50](=[O:51])[N:49]7[CH:52]=[C:53]([CH:55]8[CH2:57][CH2:56]8)[CH2:54][CH:48]7[CH:47]=[N:46][C:45]=6[CH:58]=5)[C:32]([O:34][CH3:35])=[CH:33][C:26]=4[C:25](=[O:61])[N:24]3[CH:62]=2)=[CH:17][CH:16]=1)=[O:13])=[O:9])C=C.N1CCCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C@@H:7]([CH:64]([CH3:66])[CH3:65])[C:8]([NH:10][C@@H:11]([CH3:63])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH2:22][CH:23]3[CH:29]=[N:28][C:27]4[CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]5[C:42]([O:59][CH3:60])=[CH:43][C:44]6[C:50](=[O:51])[N:49]7[CH:52]=[C:53]([CH:55]8[CH2:57][CH2:56]8)[CH2:54][CH:48]7[CH:47]=[N:46][C:45]=6[CH:58]=5)[C:32]([O:34][CH3:35])=[CH:33][C:26]=4[C:25](=[O:61])[N:24]3[CH:62]=2)=[CH:19][CH:20]=1)=[O:13])=[O:9]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(C7CC7)CC5C=N6)cc4N=CC3C2)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(C4CC4)CC1C=N3)N=CC1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Reaction time: 1 h

Procedure:
The starting material 16 (170 mg, 0.185 mmol) was dissolved in dry CH2Cl2 (5 mL) in a round bottom flask filled with argon, before pyrrolidine (41 μL, 0.21 mmol) was added. The flask was purged/refilled three times with argon before Pd(PPh3)4 (14 mg, 0.084 mmol) was added and the flushing operation repeated. After 1 hour, complete consumption of starting material was observed (the reaction was followed by LC/MS) and Et2O (50 mL) was added to the reaction mixture which was allowed to stir until all the product had crashed out of solution. The solid was filtered through a sintered funnel and washed twice with Et2O (2×25 mL). The collecting flask was replaced and the isolated solid was dissolved in CHCl3 (100 mL or until all the product had passed through the sintered funnel). The volatiles were then removed by rotary evaporation under reduced pressure to afford the crude product 17 which was used directly in the next step (168 mg). LC/MS method 2 (2.70 min (ES+) m/z (relative intensity) 830.27 ([M+H]+, 50), 660.13 (80), 171.15 (100)).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)=[CH2:2].BrN1C(=[O:17])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:17]1[CH2:2][CH:1]1[C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C2CO2)nc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 6-ethenylpyridine-3-carbonitrile (0.742 g, 5.70 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 minutes (1.07 g, 5.99 mmol) and stirred at 40° C. for 1 hour. After cooling to 5° C., the reaction was basified with drop wise addition of solution of sodium hydroxide (0.684 g in 5 mL of H2O, 17.1 mmol) and stirred for another 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated aqueous NaCl (1×30 mL) and dried over MgSO4. Evaporation of the solvent and purification over SiO2 (0-30% EtOAc/hexanes as eluent) provided 6-(oxiran-2-yl) pyridine-3-carbonitrile.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CN1CCOCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:2][CH2:3][C:4](=[O:5])[NH2:6])=[CH:22][CH:23]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NC(=O)CCBr
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(SCCC(N)=O)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 3-Bromopropionic acid amide (0.075 g, 0.5 mmol) in THF (5 ml) was added to a solution of [4-(4-mercaptophenyl)butyl]carbamic acid tert-butyl ester 560 (0.13 g, 0.46 mmol) dissolved in THF (15 mL) and 4-methylmorpholine (NMM) (0.3 mL). The reaction mixture was stirred at 50° C. for 4 h and then cooled to room temperature. Two more equivalents of 3-bromoprionic acid amide (0.15 g, 1 mmol) were added. The mixture was further stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to afford the desired product {4-[4-(2-carbamoylethylsulfanyl)phenyl]butyl}carbamic acid tert-butyl ester 570 (0.13 g, 80%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.48 (m, 2H) 1.60 (m, 2H), 2.46 (m, 2H), 2.58 (t, 2H), 3.09 (t, 2H), 3.13 (m, 2H), 7.14 (d, 2H), 7.29 (d, 2H). m/z (ESI) 353 [C18H28N2O3S+H]+.
Reaction SMILES: [O:1]([C@@H:9]([CH2:14][CH2:15][OH:16])[C:10]([O:12][CH3:13])=[O:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl>[CH2:29]([O:28][CH2:27][O:16][CH2:15][CH2:14][C@H:9]([O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])[C:10]([O:12][CH3:13])=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
(Step 2) To methyl (S)-2-(tert-butyldimethylsiloxy)-4-hydroxybutanoate (220 mg, 0.886 mmol) obtained in Step 1, dichloromethane (0.89 mL), diisopropylethylamine (0.464 mL, 2.66 mmol), and {(chloromethoxy)methyl}benzene (0.30 mL, 2.21 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80), whereby methyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (191 mg, 59%) was obtained,
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH:18][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCC[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
L-methionyl-L-proline benzylester hydrochloride (1.86 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C. and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-methionyl-L-proline benzylester (yield 1.99 g, 83.5%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].B(F)(F)F>C1C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=2)[O:13][CH:12]=[CH:11][O:3]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: OCCO
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(c2ccc(Br)cc2)OC=CO1

Procedure:
To 4-Bromoacetophenone (50.0 g., 0.25 mol) in 500 ml. benzene was added ethylene glycol (21.7 ml., 24.2 g., 0.39 mol) followed by BF3 etherate (3.69 ml., 4.26 g., 0.03 mol). The mixture was heated at reflux with a Dean-Stark trap, cooled, washed 1×350 ml. saturated NaHCO3, dried and stripped to yield title product as an oil which crystallized on standing 60.2 g., recrystallized from pentane (chilled in an acetone-dry ice bath) 43.6 g.; 1H-nmr 1.6 (s, 3H), 3.75 (m, 2H), 4.0 (m, 2H), 7.3 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN[C@H](C)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 40.2 %

Procedure:
(R)-1-(4-Bromophenyl)ethanamine (6G1) (2.10 mmol, 419 mg), methyl 2-bromoacetate (6G2) (2.10 mmol, 320 mg) and triethylamine (4.19 mmol, 424 mg) were dissolved in DCM (3 ml) and heated in the microwave at 120° C. for 20 min. The crude mixture was concentrated before purification on silica eluting with 20% EtOAc/heptane to give (R)-methyl 2-(1-(4-bromophenyl)ethylamino)acetate (6G3) 230 mg (40.1%); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H) 7.20 (d, 2H) 3.77 (q, 1H) 3.69 (s, 3H) 3.4-3.18 (dd, 2H) 1.34 (d, 3H)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@:20]32[O:23][C@H:21]3[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.CC1C=C(C)N=C(C)C=1>CCCCCCC>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1O[C@@]12CC[C@H]1[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@@]12C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To (1S,3R,17R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-17,20-epoxypregna-5-ene (100 g) obtained in Example 1, 2,2′-azobis(isobutyronitrile) (7.98 g) and γ-collidine (82.4 mL) were added, and the resulting mixture was stirred in n-heptane (1000 mL) at 75° C. for 15 minutes. After cooling the mixture to room temperature, a precipitate was removed by filtration, and the filtrate which was a solution in n-heptane was concentrated under reduced pressure. To the obtained concentrated residue containing γ-collidine, toluene (650 mL) and aluminum isopropoxide (3.64 g) were added, and the resulting mixture was heated to reflux for 2 hours. The reaction solution was cooled, and the organic layer was sequentially washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and with water, followed by concentration under reduced pressure. After suspending the obtained concentrated residue in a mixed solvent of ethyl acetate, acetonitrile and triethylamine, a precipitate was collected by filtration, washed with acetonitrile, heat-dried under reduced pressure to obtain (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-20-hydroxypregna-5,7,16-triene as slightly yellow powder (37.5 g; yield: 37.7%).
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1csc([N+](=O)[O-])c1-c1ncco1
Yield: 17.7 %

Procedure:
The above titled compound (34 mg, 18%) was synthesized from 4-bromo-5-nitrothiophene-3-carbonitrile (203 mg, 0.87 mmol) and 2-tributylstannyloxazole (0.27 mL, 1.29 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089 mmol) and copper(I) iodide (16 mg, 0.084 mmol) according to methods described herein. LCMS method [4], retention time=1.62 min; MS (ESI) 222.0 (MH+).
Reaction SMILES: N12CCN(CC1)CC2.[CH:9]1([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19](F)[CH:20]=3)[C:15](=[O:24])[C:14]([C:25]([OH:27])=[O:26])=[CH:13]2)[CH2:11][CH2:10]1.Cl.Cl.[C:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]>N1C=CC=CC=1>[C:30]([N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[C:21]3[C:16]([C:15](=[O:24])[C:14]([C:25]([OH:27])=[O:26])=[CH:13][N:12]3[CH:9]3[CH2:11][CH2:10]3)=[CH:17][C:18]=2[F:23])[CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 74.8 %

Procedure:
2.2 g (20 mmol) of 1,4-diazabicyclo[2,2,2]octane are added to a mixture of 1.33 g (5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.1 g (5 mmol) of 1-(tert.-butyl)piperazine dihydrochloride in 12.5 ml of pyridine, and the mixture is heated under reflux for 3 hours. It is concentrated in vacuo, the residue is stirred with 25 ml of water and the pH is brought to 5 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and recrystallized from glycol monomethyl ether. 1.45 g (75% of theory) of 7-(4-tert.-butyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 257°-260° are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8]([OH:10])=[O:9])=O.[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:10]1)[CH3:39]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1
Yield: 52.4 %

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (44.9 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (29.7 g.) and acetic anhydride (50 ml.) was heated (at 85°-90° C.) during 3 hours. The resulting crystalline product was washed with methanol, slurried in hot ethanol and washed again with methanol, affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = Cl) (34.1 g., m.p. 162°-164° C.).
Reaction SMILES: O=[C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].O>C(O)C>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:2]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2cccs2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.3 %

Procedure:
Ethyl 3-oxo-3-(2-thienyl)propanoate (500 mg, 2.50 mmol) and 4-azido-N-ethylbenzamide (500 mg, 2.50 mmol, 1.0 eq.) obtained in Example 43a) were dissolved in ethanol (20 ml), a solution of sodium ethoxide in ethanol (20%, 1.3 g, 3.82 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 7 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1). The organic layer was extracted with 2% aqueous sodium carbonate solution. The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (764 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28](O)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:27][C:28](=[O:29])[NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (10 ml) was dissolved 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). The resulting mixture was heated overnight under reflux. After cooling to room temperature, methanesulfonamide (415 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting mixture was washed successively with 1N hydrochloric acid, and saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×10.0 cm, dichloromethane:methanol=100:1), whereby the title compound (518 mg, 44%) was obtained as colorless foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([O:16][C:17]([C:19]1[CH:24]=[C:23]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[N:10]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(C(=O)O)c(Cl)n2)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
2,6-Dichloronicotinic acid (1.20 g, 6.25 mmol), 3-(tert-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1,2-dimethoxyethane (30 mL) and water (0.5 mL) were combined under an argon atmosphere and the mixture heated at 90° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The aqueous layer was acidified to pH 3-4 using 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert-butoxycarbonyl)phenyl)-2-chloronicotinic acid (1.4 g, 67%) as an off-white foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.59 (t, 1H), 1.60 (s, 9H); m/z 334 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:18][CH2:17][C:11]1([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: N#CC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Temperature: 70 °C
Reaction time: 14 h
Yield: 30.7 %

Procedure:
To a stirred solution of 1-(1H-indazol-5-ylamino)-cyclohexanecarbonitrile (2.53 g, 10.5 mmol) in THF (40 mL) at room temperature and under nitrogen was added LiAlH4 (21.0 mL of a 1.0 M solution in THF, 21.0 mmol) dropwise over 3 minutes. After 30 minutes the reaction mixture was warmed to 70° C. After 2 hours the reaction mixture was cooled and stirred at ambient temperature for 14 hours, then quenched by the addition of sodium sulfate decahydrate (3 g). The reaction mixture was diluted with DCM:MeOH:NH4OH (90:9:1, 200 mL) then filtered and concentrated in vacuo. Purification by chromatography (silica, 3 to 20% of a 9:1 MeOH:NH4OH solution in DCM) gave (1-aminomethyl-cyclohexyl)-(1H-indazol-5-yl)-amine (0.785 g, 3.22 mmol, 31 %) as a solid.