Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C.O>[C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:7][CH:8]=1
Reactant: Clc1ncnc2ccccc12
Reactant: OCCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 0.53 g of sodium hydride in 200 ml of DMF was added 2.2 g of 2-[(1,1'-biphenyl)-4-yl]ethanol, and the mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature for another three hours. The mixture was then poured into a mixture of ice in water. The solid phase was collected and washed with water. TLC showed two spots. The product was purified using HPLC (silica gel, CH2Cl2) giving 1.1 g of the title product. Yield: 30.6%. M.P. 72°-74° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[N:15]=[CH:14][C:13]2=[CH:22][CH:23]=[CH:24][N:12]12.[Cl-].[NH4+]>O1CCCC1>[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[NH:15][CH:14]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[C:13]2=[CH:22][CH:23]=[CH:24][N:12]12
Reactant: CN1CCC(Cl)CC1
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2Nc3cnccc3N(C)n3cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a warm Grignard reagent prepared from 7.2 g of 4-chloro-1-methyl piperidine and 1.4 g of magnesium metal in 50 ml of tetrahydrofuran was added a solution of 5.3 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 15 minutes, added to an iced ammonium chloride solution and extracted with ethyl acetate (3×). The combined organics were washed with water (2×) followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% methanol/dichloromethane). Recrystallization from ethyl acetate)methanonl (20:1) afforded 1.65 g of 10,11-dihydro-5-methyl-10-[(1-methyl)piperidin-4-yl]-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp: 235°-238° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:44])[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][N:33]2C(=O)C3C(=CC=CC=3)C2=O)[CH:17]=[CH:18][CH:19]=1.O.NN.C(O)C>>[NH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)=[O:44]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN3C(=O)c4ccccc4C3=O)c2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN)c2)C1
Temperature: 25 °C

Procedure:
Into a 100-mL round-bottom flask, was placed N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanamide (870.0 mg, 1.36 mmol, 1.00 equiv) and 1M hydrazine monohydrate in ethanol (30.0 mL, 30.0 mmol). The resulting solution was heated at reflux for 1 hour. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residual solution was diluted with 30 mL of water and then extracted with 3×50 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (100˜50:1˜10:1˜1:1). This resulted in 600 mg (85%) of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)propanamide as a pale yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>C(O)C.N1CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (60.9 mg, 53%).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@@H:65]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:70]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
To a solution of ethyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (18, 200 mg, 0.48 mmol), DCC (120 mg, 0.58 mmol) and DMAP (6 mg, 0.048 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (161 mg, 0.48 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (6 mL) and cooled to 0° C. Dimethylamine (6 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 140 mg (55%) of the title compound as a colorless semi solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([O:19]C)=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][C:32]=1[O:39][CH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[C:32]([O:39][CH3:40])[CH:33]=2)=[O:19])[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1cc(CN)ccc1F
Reactant: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)nc(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(CNC(=O)c2cc(CO[Si](C)(C)C(C)(C)C)nc(C)n2)ccc1F
Temperature: 70 °C
Yield: 81.2 %

Procedure:
To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(N)=O)s1
Reaction time: 2.25 h
Yield: 83.8 %

Procedure:
A solution of 2.20 g (7.01 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid, 38 mL of dimethylformamide, 3.47 g (8.85 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.75 mL (21.53 mmole) of ethyldiisopropylamine was stirred at room temperature for 23 minutes, then 0.5733 g (10.72 mmole) of ammonium chloride was added. The mixture was stirred for 2.25 hours, then concentrated under reduced pressure and partitioned between 300 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed twice with 60 mL of water, twice with 55 mL of saturated aqueous sodium bicarbonate, once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100-:0) to give 1.841 g 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]=[N+]=[N-])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H].N.CCOC(C)=O>CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:10][C@H:11]([NH2:13])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N=[N+]=[N-])C1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N)C1
Yield: 100.5 %

Procedure:
To the mixture of tert-butyl(trans-3-azidocyclobutyl)methylcarbamate (1.8 g, 7.95 mmol) and Pd/C (200 mg) in MeOH (5 mL) under hydrogen atmosphere (hydrogen balloon) was added NH3(g)/MeOH (saturated, 50 mL) via syringe. The resulting mixture was stirred at rt for three hours until TLC analysis (EtOAc:petroleum ether=1:2) showed the reaction was complete. Pd/C was filtered off and the resulting solution was concentrated and dried in vacuum to afford crude title compound (1.6 g), which was used for the next steps without further purification.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (167 mg) in acetonitrile (15 mL) were added sodium iodide (134 mg) and chloro(trimethyl)silane (0.452 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (142 mg).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@@H:18]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:20]([C:29]3[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=3)[C:19]2=[O:36])=[CH:11][CH:10]=1.[CH2:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:39]#[CH:40]>CN(C=O)C.[Cu]I>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@H:18]2[C:19](=[O:36])[N:20]([C:29]3[CH:34]=[CH:33][C:32]([C:40]#[C:39][CH2:38][NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[C@@H:21]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: C#CCNS(C)(=O)=O
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(O)cc2)N1c1ccc(I)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O)cc2)cc1

Procedure:
Triethylamine (7 equivalents) is added to a solution of (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-1-(4-iodophenyl)azetidin-2-one (i-6) (1.00 equivalent), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (1.50 equivalents), tetrakistriphenylphosphine palladium(0) (0.15 equivalents) and copper(I) iodide (0.30 equivalents) in DMF (0.1 M concentration with respect to final product) under a nitrogen atmosphere and the resulting solution aged at room temperature. After completion of reaction, the volatiles are evaporated in vacuo and the crude residue can be purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:15]1[CH2:19][CH2:18][C:17]2([CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:16]1)[CH3:14].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[CH2:13]([N:15]1[CH2:19][CH2:18][C:17]2([CH2:20][N:21]([C:2]3[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:16]1)[CH3:14]
Reactant: CCN1CCC2(CCNC2)C1
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CCN1CCC2(CCN(c3cc(C)c(N)c([N+](=O)[O-])c3)C2)C1
Temperature: 90 °C
Yield: 59.8 %

Procedure:
A suspension of 4-iodo-2-methyl-6-nitroaniline (1.39 g, 5 mmol), 2-ethyl-2,7-diaza-spiro[4.4]nonane (770 mg, 5 mmol), CuI (190.5 mg, 1.0 mmol), ethylene glycol (931 mg, 15 mmol) and K3PO4 (3.2 g, 15 mmol) in isopropanol (40 mL) was sealed and heated at 90° C. for 19 h. After cooled down to room temperature, the reaction mixture was concentrated. The residue was purified by chromatography (16:1 CH2Cl2/MeOH) to afford the title compound (910 mg, 60%). 1H NMR (CDCl3) δ 1.29 (t, J=8 Hz, 3H), 1.96-2.19 (4H), 2.24 (s, 3H), 2.77-3.01 (6H), 3.22-3.40 (4H), 5.78 (br s, 2H NH), 6.80 (s, 1H), 7.06 (s, 1H). ESI-MS m/z 305 (MH+).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)C=C.[C:17]1(OC2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1>>[CH2:22]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[OH:4])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:17]=[CH2:18]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccnc2ccc(OC)cc12
Product: C=CCc1cnc2ccc(OC)cc2c1O
Yield: 32 %

Procedure:
A solution of 4-allyloxy-6-methoxy-quinoline (4.0 g, 18.6 mmol, 1.0 eq) in diphenyl oxide (80 mL) is heated at 180° C. for 1 hour. The reaction mixture is then cooled down to room temperature before the addition of petroleum ether (100 mL). The resulting suspension is filtered to afford 3-allyl-6-methoxy-quinolin-4-ol as a light grey solid (1.3 g, 32% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15]C)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl>C1COCC1.O>[I:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]([O:2][CH3:1])[OH:15])[N:6]=[CH:7]2
Reactant: COC(Cn1ncc2cc(I)ccc21)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(O)Cn1ncc2cc(I)ccc21
Temperature: 70 °C
Yield: 83.6 %

Procedure:
To a solution of 1-(2,2-dimethoxyethyl)-5-iodo-1H-indazole (920 mg, 2.77 mmol) in THF (20 mL) at 40° C. was added 2M HCl (20 mL). The solution was heated at 70° C. for 18 h. The reaction mixture was cooled and diluted with H2O (60 mL). The aqueous mixture was extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated to yield the title compound (737 mg, 88%) as a light brown solid: ESI MS m/z 318 [M+H]+.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: CCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCCC)c4ccccc4)ccc3n2C)cc1
Yield: 31 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 31% of theory, C36H44N6O5 (640.8); Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=641; (M+H+Na)++=332; (M+Na)+=663.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][CH2:14][NH:15][C:16](N1C=CN=C1)=[O:17])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:5]=12)([CH3:2])[CH3:3]
Reactant: CC(C)c1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)c1c2n(c3ccccc13)C(=O)NCC2
Yield: 33.8 %

Procedure:
A mixture of N-[2-(3-isopropylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.0 g), 1.8-diazabicyclo[5.4.0]-undec-7-ene (1 g) and toluene (100 ml) was reflux for 1 hour. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-isopropylpyrimido[1,6-a]indol-1(2H)-one (0.52 g).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[CH2:29]>>[N:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:17][CH2:16][CH:15]([NH:14][N:11]3[CH2:12][CH2:13][C@H:9]([NH:8][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH:28]=[CH2:29])=[CH:31][CH:32]=4)(=[O:38])=[O:37])[C:10]3=[O:27])[CH2:20][CH2:19]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Product: C=Cc1ccc(S(=O)(=O)N[C@H]2CCN(NC3CCN(c4ccncc4)CC3)C2=O)cc1
Yield: 78.2 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 4-vinylbenzenesulfonyl chloride (105 mg), the title compound (179 mg) was obtained as a colorless amorphous material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Reaction time: 2 h

Procedure:
18 g (62.6 mmol) of 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) and 11 g (68.9 mmol) of (2-(4-amino-phenyl)-2-methyl-propionitrile (Example 1e) are dissolved in 350 ml of acetic acid and stirred for 2 h. After this time, water is added and the yellow precipitate is filtered off and washed with H2O. The solid is dissolved in EtOAc-THF (1:1), washed with sat. aqueous NaHCO3 and dried over MgSO4. The organic phase is evaporated to dryness to give the title compound as a yellow solid. ES-MS: 411, 413 (M+H)+, Br pattern; analytical HPLC: tret=3.69 min (Grad 1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH3:38])[CH:29]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[C:30]([CH3:38])[CH:29]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(3-methyl-4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.21 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 68%). MS (ISP) 484.2 [(M+H)+]; mp 222.5° C.