Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12](B(O)O)[N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:30]([F:33])([F:32])[F:31])[N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(OCc3ccccc3)cccc21
Product: CC(C)(C)OC(=O)n1c(C(F)(F)F)cc2c(OCc3ccccc3)cccc21

Procedure:
[4-(Benzyloxy)-1-(tert-butoxycarbonyl)-1H-indol-2-yl]boronic acid and trimethyl(trifluoromethyl)silane were combined to give tert-butyl 4-(benzyloxy)-2-(trifluoromethyl)-1H-indole-1-carboxylate, which was debenzylated via ammonium formate transfer hydrogenation to give tert-butyl 4-hydroxy-2-(trifluoromethyl)-1H-indole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:15]2[CH:10]3[CH2:11][CH2:12][CH:13]2[CH2:14][N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:9]3)=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Clc1cccnc1N1CC2CCC(C1)N2
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2C3CCC2CN(c2ncccc2Cl)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (129 mg, 577 μmol) in dry dichloromethane (5 mL) was treated with 1-tert-butyl-4-isocyanatobenzene (101 mg, 577 μmol) and allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z: 399 (M+H)+; 1H NMR (CDCl3) δ 1.30 (s, 9H), 2.01 (m, 2H), 2.17 (m, 2H), 3.25 (d, 2H), 3.64 (dd, 2H), 4.38 (dd, 2H), 6.32 (s, 1H), 6.86 (dd, 1H), 7.32 (s, 4H), 7.59 (dd, 1H), 8.17 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].I.CS[C:19](=[NH:28])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[NH:28][C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: NNC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSC(=N)Nc1ccc(O)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(Nc2nnc(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
4-chloro-3-trifluoromethylbenzoic acid hydrazide (2.89 g, 12.1 mmol) and S-methyl N-(4-hydroxyphenyl)isothiourea hydroiodide (3.75 g, 12.1 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a white solid (1.95 g). Yield 45.5%.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH:20]5[CH:21]6[CH:15]3[CH:16]3[CH:19]4[CH:18]5[C:17]36[C:22](O)=[O:23])[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[BH4-].[Na+].Cl>CC#N>[OH:23][CH2:22][C:17]12[CH:18]3[CH:19]4[C:14]5([C:7]6[NH:6][C:5]7[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=7[N:8]=6)[CH:20]3[CH:21]1[CH:15]5[CH:16]24
Reactant: CCCn1c(=O)c2[nH]c(C34C5C6C3C3C4C5C63C(=O)O)nc2n(CCC)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)c2[nH]c(C34C5C6C3C3C4C5C63CO)nc2n(CCC)c1=O
Reaction time: 3 h

Procedure:
To a stirred suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-1-carboxylic acid (100 mg, 0.261 mmol) and HATU (1.1 eq, 0.288 mmol, 110 mg) in 6 ml of MeCN was added Hunig's base (1.1 eq, 0.288 mmol, 37 mg), neat via syringe. The resulting heterogeneous mixture was stirred for 3 h and NaBH4 (2.0 eq, 0.522 mmol, 20 mg) was added in one portion. The mixture was stirred for an additional 2 h, cooled with the aid of an ice bath and acidified by the dropwise addition of concentrated HCl. The resulting pale yellow precipitate was collected, dried, and resuspended in MeCN. After stirring overnight the material was collected and dried to afford an off-white powder (50 ma, 52%). MS: 369 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:5]([S:2](=[O:4])(=[O:3])[N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:26])[CH:6]=1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CNC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (2.0 g, 7.56 mmol) and diisopropylethylamine (1.94 ml, 11.34 mmol) in DCM (50 ml) is treated with N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) at 0° C. The solution is stirred at room temperature for 3 hours and N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) is added. The solution is partitioned between DCM (250 ml) and 0.5 N HCl (100 ml). The organic layer is washed with 0.5 N HCl (2×100 ml), sat. aq. NaHCO3 (2×100 ml) and water (100 ml), dried over MgSO4, and the solvent removed in vacuo to yield a yellow oil. Crystallisation (iPr2O/EtOAc) yields 3-(Cyclohexyl-methyl-sulfamoyl)-4-methoxy-benzoic acid methyl ester as yellow crystals; [M+H]+ 342.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[O:19][C:20]1[C:25]([N:26]=[C:27]=S)=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[N:21]=1)([CH3:16])([CH3:15])[CH3:14]>ClCCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:27]([NH:26][C:25]3[C:20]([O:19][C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=3)[NH:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N=C=S)c(Oc2ccccc2C(C)(C)C)n1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: ClCCCl
Product: COc1ccc(Nc2nc3ccc(C(C)(C)C)cc3[nH]2)c(Oc2ccccc2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(tert-butyl)-1,2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 2c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 2d and 2d′ was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3CCCC[O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)O>C(O)=O.[Zn]>[CH:15]([O:14][CH2:13][CH2:12][CH2:11][N:8]1[C:9](=[O:10])[C:4]2[C:3]([CH2:25][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[C:2]([Br:1])[CH:24]=[N:23][C:5]=2[N:6]([CH3:22])[C:7]1=[O:21])=[O:16]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Temperature: 60 °C
Yield: 10 %

Procedure:
To a solution of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (800 mg, 1.50 mmol) in HCOOH (10 mL) was added Zn dust (484 mg, 7.50 mmol). The reaction was heated at 60° C. for 2 h cooled to RT and filtered. The filtrate was concentrated to give 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (70 mg, 10% yield) as an oil. LCMS: MH+ 466 and TR=1.753 min. Used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[C:14]([F:17])([F:16])[F:15])([O-])=O.Cl[Sn]Cl>Cl.CCO>[F:17][C:14]([F:15])([F:16])[C:9]1[C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2c(C(F)(F)F)ccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 79.9 %

Procedure:
In a similar fashion using route 2 general procedure 4, 8-nitro-4-trifluoromethyl-quinoline 468 (900 mg, 4.13 mmol), SnCl2 (3.12 g, 16.5 mmol), 6N HCl (2 drops) and EtOH (20 ml) at 85° C. for 3 h gave the title compound (700 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH2:12][O:11][C@H:10]1[N:31]1[CH:38]=[C:37]([F:39])[C:35](=O)[NH:34][C:32]1=[O:33])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl.C[OH:48]>C(Cl)Cl.O>[C@@H:10]1([N:31]2[C:38](=[O:48])[C:37]([F:39])=[CH:35][NH:34][C:32]2=[O:33])[O:11][CH2:12][C@H:13]([OH:23])[C@H:14]([OH:15])[C@@H:9]1[OH:8]
Reactant: O=c1[nH]c(=O)n([C@@H]2OC[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1F
Reactant: CO
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]cc(F)c(=O)n1[C@@H]1OC[C@H](O)[C@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of 17 (from Part D) (2.42 g, 4.54 mmol) in CH2Cl2 (100 ml), at -78° C. under nitrogen atmosphere, 1M solution of BCl3 (50 ml, 49.94 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 4 h and 1:1 mixture of CH2Cl2 /MeOH (100 ml) was added and the reaction mixture was brought to room temperature and the solvents were evaporated to dryness. The residue was coevaporated with MeOH (50 ml) 5 times. The residue obtained was dissolved in water and washed with CHCl3 (50×2) and CCl4 (50 ml). The water layer was evaporated to give a white solid and which was crystallized from EtOH/ether to give the pure 18 (0.94 g, 79.4%) as white crystals: mp 231° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 2-chloronicotinic acid (37.8 g, 0.240 mol) in dry DCM (150 mL) and DMF (0.1 mL) cooled in an ice-bath was added oxalyl chloride (22.9 mL, 0.264 mol) dropwise over a period of 15 min. After stirring for 1 h at 0° C., the reaction mixture was heated to reflux for 6 h (the mixture became a clear brownish solution). The solvent and the excess oxalyl chloride was evaporated under reduced pressure. Toluene (100 mL) was added to the residue and the mixture was evaporated. The obtaining residue was purified by vacuum distillation to give 2-chloronicotinoyl chloride (41.7 g, 99%); bp 98–100° C./2 mmHg, mp 38–39° C. (from Lancaster catalog). Caution: Distillation may need a special care due to the high melting point of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103 %

Procedure:
Mix 5-bromo-2-fluoro-nitrobenzene (10 g, 45 mmol) and 4-(2-aminoethyl)morpholine (11.8 mL, 90 mmol) in THF (100 mL). Stir at room temperature for 18 h. Remove the THF under reduced pressure and partition the residue between water (200 mL) and ethyl acetate (200 mL). Dry the organic layer (MgSO4) and concentrate to give 15.3 g (100%) title compound. HPLC (ISO80-10M) t=1.83 min (94%), MS (S) 331 (M+1).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][N:32]([CH3:36])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:35]#[C:34][CH2:33][N:32]([CH3:36])[CH3:31])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: C#CCN(C)C
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C#CCN(C)C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (122 mg, 0.233 mmol), N,N-dimethyl-2-propyn-1-amine (0.037 mL, 0.349 mmol), copper(I) iodide (4.44 mg, 0.023 mmol), bis(triphenylphosphine)palladium(II) chloride (6.54 mg, 9.32 μmol) and triethylamine (0.097 mL, 0.699 mmol) in THF (1.0 mL) was stirred under an atmosphere of nitrogen at 70° C. for 3 h. The mixture was allowed to cool to RT and was then partitioned between saturated aqueous NaHCO3 (25 mL) and ethyl acetate (75 mL). The aqueous phase was separated and extracted with additional ethyl acetate (25 mL). The organic extracts were combined, washed with brine (25 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-10% MeOH in DCM, and then further purified on silica, eluting with a gradient of 0-10% 2M NH3 in MeOH in DCM to afford the title compound (4.9 mg). 1H NMR (MeOD, 400 MHz) δ ppm: 2.42 (6H, s), 2.55 (3H, s), 3.80 (5H, s), 6.89 (2H, m), 7.01 (1H, d, J=7.7 Hz), 7.26 (1H, s), 7.32-7.48 (3H, m), 7.49-7.60 (2H, m).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)=[S:37])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCN1CCN(CCNC(=O)c2nn(CCC)c3ccccc23)CC1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(CCNC(=S)c2nn(CCC)c3ccccc23)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of N-[2-(4-n-butyl-1-piperazinyl)-ethyl]-1-n-propylindazole-3-carboxamide (0.39 g) obtained in Example 3 in toluene (10 ml) was added Lawesson reagent (0.64 g) at room temperature, and the mixture was heated under reflux for one hour. The reaction solution was cooled to room temperature, diluted with chloroform (50 ml), and then washed with saturated aqueous sodium hydrogencarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel (chloroform:methanol:aqueous ammonia=8:2:0.2) to give the title compound (0.36 g) as a pale yello; oily substance. Yield=88%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[C:17]3[N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=4)[N:14]=[CH:13][C:12]=3[CH2:11][CH2:10][C:9]=2[N:29]=1)=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[C:17]3[N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N:29]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2c(s1)-c1nc(Nc3cccc(S(N)(=O)=O)c3)ncc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc3c2s1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A suspension of 8-(3-Sulfamoyl-phenylamino)-4,5-dihydro-thiazolo[4,5-h]quinazoline-2-carboxylic acid ethyl ester (609 mg, 1.41 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (480 mg, 2.12 mmol) in anhydrous 1,4-dioxane (30 mL) was refluxed under nitrogen for 2 hours. The reaction mixture was cooled down to room temperature and the DDQ residues were filtered. The mother liquor was concentrated in vacuo and the resulting crude residue was triturated in a mixture of EtOAc, MeOH and DCM. The resulting solid was filtered to afford 523 mg (86% yield) of the title compound as a yellow solid. MS (ES+) 430, (ES−) 428. δH (d6 DMSO) 1.42 (3H, t), 4.51 (2H, q), 7.37 (2H, s), 7.52 (1H, d), 7.60 (1H, t), 8.09 (1H, d), 8.14 (2H, s), 8.70 (1H, s), 9.55 (1H, s), 10.59 (1H, s).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O1CCOCC1>Cl>[C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)O[C@@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reaction time: 1 h

Procedure:
A solution of (R)-tert-butyl 8-acetoxy-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (62 mg, 0.139 mmol) in 4M HCl in dioxane (1.252 ml, 5.01 mmol) was left to stir under an atmosphere of nitrogen for 1 hour. The reaction mixture was concentrated in vacuo to afford (R)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBR) which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:36])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:36])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccc(C(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M161) (133 mg, 0.26 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (61 mg, 58%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][N:15]([C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CNC1c2ccccc2CCC1N1CCCC1
Product: CN(C(=O)Cc1ccc([N+](=O)[O-])cc1)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 92 %

Procedure:
Using the procedure of Step C of Example 1, 770 mg of (p-nitrophenyl) acetic acid and 700 mg of the product of Step B of Example 1 were reacted to obtain 1.4 g of crude product which was purified by chromatograph on silica (eluant: methylene chloride 90, methanol 10) to obtain 1.1 g of product which was crystallized from ethyl ether to obtain 480 mg of product. Two crystallizations from isopropanol were effected to obtain 300 mg of the expected product melting at 135° C.
Reaction SMILES: [F:1][CH:2]([F:25])[N:3]1[C:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([I:18])=[CH:13][C:12]=4[C:6]=2[N:5]=[C:4]1[C:20]([O:22]CC)=O)[CH2:9]3.[NH3:26]>>[F:25][CH:2]([F:1])[N:3]1[C:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([I:18])=[CH:13][C:12]=4[C:6]=2[N:5]=[C:4]1[C:20]([NH2:26])=[O:22])[CH2:9]3
Reactant: CCOC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: N
Product: NC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 80 %

Procedure:
A pressure tube containing a solution of ethyl 3-(difluoromethyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (11 mg, at 52% purity LCMS-UV215) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 36 hr. Evaporation of the reaction mixture furnished the title compound (12 mg at 80% purity LCMS-UV215) as a colorless solid which was carried through to the next synthetic step without purification: 1H NMR (500 MHz, CDCl3) δ 1.70-1.16 (m, 2H), 2.95-3.02 (m, 2H), 3.59 (td, J=8.2, 3.5 Hz, 1H), 3.86-3.91 (m, 1H), 5.58 (br. s, 1H), 6.86 (d, J=8.6 Hz, 1H), 7.40 (br. s, 1H), 8.71 (d, J=6.6 Hz, 1H), 8.75 (t, J=58.6 Hz, 1H); M+H=434.
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(CO)c[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc(C=O)c[nH]1

Procedure:
A 7.7 gm. portion of 2-tert-butyl-4-imidazolemethanol is added to 100 ml. of chloroform and 100 ml. of tetrahydrofuran and heated gently. A 25 gm. portion of manganese dioxide is added and the mixture is reacted as described in Example 22 giving the desired product as white crystals, m.p. 194°-195° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CC(C)=O.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C(N(CC)CC)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(=O)Nc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 66 %

Procedure:
33.3 g of propionyl chloride were added over 30 minutes at 20°-30° C to a mixture of 480 ml of acetone, 48.3 g of o-trifluoromethyl aniline and 36.42 g of triethylamine and after standing for 12 hours, the mixture was filtered. The acetone was evaporated from the filtrate and the residue was taken up in 500 ml of ethyl acetate. The solution was washed with 10% potassium carbonate solution, then with water until the pH of the wash waters was 6, then with N hydrochloric acid and then with water until the wash water pH was 6. The solution was dried over magnesium sulfate, treated with activated carbon and then evaporated to dryness to obtain 65 g of raw product which was washed with iced essence G to obtain 43 g of N-(2-trifluoromethylphenyl)-propanamide melting at 86° C.