Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][C:22]1=[O:31].[Al+3].[Cl-].[Cl-].[Cl-].Cl>O1CCCC1.CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:31])[N:21]([CH3:20])[C:26]=2[CH:27]=1)=[O:13]
Reactant: CN1C(=O)COc2ccccc21
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(Cl)c(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of (2-chloro-5-methoxy-phenyl)-acetic acid (1 g) in tetrahydrofuran (20 ml) were added N,N-dimethylformamide (2 drops) and oxalylchloride (1.03 g). The mixture was stirred overnight at room temperature. The solvent was evaporated; toluene was added and again evaporated. The residue was dried under high vacuum to give the crude acid chloride. To a cooled solution (ice bath) of 4-methyl-2H-1,4-benzoxazin-3(4H)-one (830 mg) in 1,2-dichloroethane (5 ml) was added AlCl3 (1.99 g). The mixture was stirred for 10 min and a solution of the acid chloride in 1,2-dichloroethane (5 ml) was added dropwise. The mixture was stirred at 0° C. for 4.5 h. The mixture was poured into ice water and hydrochloric acid and extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (1.6 g) as an off-white solid. MS (m/e)=346.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH:32]([C:34]#[N:35])[CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([NH:43][CH:44]2[CH2:47][O:46][CH2:45]2)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:34]([CH:32]1[CH2:33][CH:30]([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:36][C:37]3[CH:49]=[CH:48][C:40]([C:41]([NH:43][CH:44]4[CH2:45][O:46][CH2:47]4)=[O:42])=[CH:39][C:38]=3[O:50][CH3:51])[N:3]=2)[CH2:31]1)#[N:35]
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(C#N)C4)c23)cc1
Reactant: COc1cc(C(=O)NC2COC2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CC(C#N)C4)c23)cc1
Temperature: 110 °C
Yield: 55 %

Procedure:
A mixture of 4-(2-chloro-4-(3-cyanocyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.2 equiv), 2,2′-Bis(diphenylphosphino)-1,1′-binapthalene (0.2 equiv), cesium carbonate (5 equiv), and palladium acetate (0.1 equiv) in 1,4-dioxane (0.2 M) was purged with nitrogen and sealed. The reaction mixture was heated to 110° C. for 2 h. The reaction was filtered and solvents were removed under reduced pressure. The reaction mixture was purified using silica gel chromatography (0 to 100% ethyl acetate in hexane) to give the title compound (55% yield). MS (ESI) m/z 698.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.ClC1C=CC(OC)=CC=1N.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:42]3[CH2:41][CH2:40][N:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:38]=4[N:29]=[CH:30][CH:31]=[CH:32]5)[CH2:44][CH2:43]3)[CH2:17][CH2:18]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc(N2CCNCC2)c2ncccc12
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(Cl)c(N)c1
Agent: [Na+]
Product: COc1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-methoxy-8-(piperazin-1-yl)quinoline (prepared from 2-chloro-5-methoxyaniline using the methodology described for the preparation of Example N, Step 3, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a beige solid; MP. 218-220° C.; MS (ES) m/z (relative intensity) 454 (M+H)+ (100).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:28])[CH2:2][CH3:3].Br[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:33]([CH2:32][CH2:31][CH2:30][O:28][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:12][C:13]=2[C:4]=1[CH2:1][CH2:2][CH3:3])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCCOc1ccccc1
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 370 mg (0.941 mmol) of the title product of Example 44, 243 mg (1.13 mmol) of 1-bromo-3-phenoxypropane, and 273 mg (1.98 mmol) of anhydrous potassium carbonate in 10 ml of dimethylformamide was stirred overnight at room temperature. Thereafter, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated, acidified with 3N hydrochloric acid, and the layers reshaken. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The title compound (185 mg) was obtained after chromatography on silica gel using 20% ethyl acetate/hexane as eluent.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH:10]=[C:9]([C:24]2[C:32]3[O:31][CH2:30][O:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13]1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: Brc1cccc2c1OCO2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2OCO3)CC1
Temperature: 85 °C
Yield: 80.9 %

Procedure:
Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.62 g, 5.22 mmol) was added to a solution of 4-bromobenzo[d][1,3]dioxole (1 g, 4.97 mmol) in 1,2-Dimethoxyethane (45.0 ml) and Na2CO3 2M (8.28 ml, 16.6 mmol). The resulting suspension was degassed using a stream of argon in an ultrasonic bath during 5 min. Then triphenylphosphine (261 mg, 995 μmol) and palladium (II) acetate (112 mg, 497 μmol) was added and the reaction mixture was stirred over night at 85° C. The reaction was cooled to rt, diluted with 40 mL of water and the mixture extracted with ethyl acetate (3×50 mL). The organic layers were dried over MgSO4 and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield 4-Benzo[1,3]dioxol-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellowish liquid (1.22 g, 80.8%). MS (ISP) m/z=304.4 [(M+H)+].
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=O)(C)(C)C>O1CCOCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:9]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2)c1
Reaction time: 2.5 h
Yield: 72.9 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.65 g of (S)-1-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 2.5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting oily residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 910 mg (yield 73%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([CH3:26])[C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24]
Reactant: CNCCO
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CN(CCO)C(=O)c1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methylamino-ethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]1[C:24]1[CH:25]=[C:26](C)[CH:27]=[CH:28][CH:29]=1.O=[C:32]1C(C(O)=O)CCN1C1C=C(C)C=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:32])[C:16]1=[O:15])=[O:23]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1cccc(N2CCC(C(=O)O)C2=O)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 44.3 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid (0.095; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.076 g (44%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-o-tolylpyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:23])([CH3:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)=[CH:5][C:4]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.[NH2:35][S:36](Cl)(=[O:38])=[O:37]>CC(N(C)C)=O>[S:36](=[O:38])(=[O:37])([O:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[CH2:10][N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:8]([CH3:23])([CH3:22])[CH2:7]2)[NH2:35]
Reactant: NS(=O)(=O)Cl
Reactant: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(CN2Cc3cc(OC)c(OS(N)(=O)=O)cc3CC2(C)C)c1
Yield: 89 %

Procedure:
Sulfamoylation of 226 with H2NSO2Cl and DMA as described above afforded the title compound (86 mg, 89%) as a colourless foam. 1H NMR (400 MHz; DMSO-d6) 1.14 (6H, s, 2×CH3), 2.69 (2H, s, CH2), 3.43 (2H, s, CH2), 3.62 (2H, s, CH2), 3.73 (3H, s, OCH3), 3.75 (3H, s, OCH3), 6.80 (1H, dd, J=8.0, 2.0 Hz, CH), 6.83 (1H, s, CH), 6.89-6.94 (3H, m, 3×CH), 7.23 (1H, t, J=8.0 Hz, CH), 7.79 (2H, s, NH2). 13C NMR (100 MHz; DMSO-d6) 42.80 (CH2), 49.42 (CH2), 52.05 (C), 53.0 (CH2), 54.94 (OCH3), 55.79 (OCH3), 111.83 (CH), 112.97 (CH), 114.10 (CH), 120.30 (CH), 120.61 (CH), 125.77 (C), 129.25 (CH), 133.04 (C), 136.80 (C), 142.19 (C), 149.88 (C), 159.28 (C). LC/MS (ES+) tr=1.14 min, m/z 407.28 (M++H). HRMS (ES+) cald. for C20H27N2O5S (M++H) 407.1635, found 407.1636. HPLC tr=2.10 min (>98%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([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: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 85 °C
Yield: 16.6 %

Procedure:
To a stirred mixture of methyl 4-bromobenzoate (1.00 g) and 3-nitrophenylboronic acid (800 mg) in dioxane (20 mL) was added tetrakis(triphenylphosphine)palladium(0) (165 mg) and solid sodium carbonate (710 mg). The mixture was heated at 85° C. overnight, cooled to room temperature and partitioned between dichloromethane (100 mL) and 2 M aqueous sodium carbonate (50 mL) containing concentrated ammonium hydroxide (5 mL). The aqueous layer was further extracted twice with dichioromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica and chromatographed on silica gel eluting with 6:94 ethyl acetate in hexane to provide the title compound (198 mg) as a white solid
Reaction SMILES: Br[C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[OH:11].[N-:12]=[N+:13]=[N-:14].[Na+].CCOC(C)=O.O>CS(C)=O>[N:12]([CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[OH:11])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1Cc2ccccc2[C@@H]1O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
trans-2-Bromo-1-indanol (2 g, 9.39 mmol) and sodium azide (0.915 g, 14.08 mmol) were combined in DMSO (20 mL) and stirred at 75° C. for 3 hours. The mixture was worked up with EtOAc and H2O, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[S:28][C:27]([NH2:29])=[N:26][C:13]=2[N:14]=[C:15]([S:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[N:16]=1.[NH2:30][C@H:31]([CH2:34][C:35]([F:38])([CH3:37])[CH3:36])[CH2:32][OH:33]>CN1C(=O)CCC1>[NH2:29][C:27]1[S:28][C:12]2[C:11]([NH:30][C@H:31]([CH2:34][C:35]([F:38])([CH3:37])[CH3:36])[CH2:32][OH:33])=[N:16][C:15]([S:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:14][C:13]=2[N:26]=1
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Reactant: CC(C)(F)C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](Sc1nc(N[C@@H](CO)CC(C)(C)F)c2sc(N)nc2n1)c1ccccc1
Temperature: 120 °C
Reaction time: 22 h
Yield: 34.3 %

Procedure:
DIPEA (0.83 mL, 4.75 mmol) was added to a solution of 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (0.49 g, 1.52 mmol) and (2R)-2-amino-4-fluoro-4-methylpentan-1-ol (2 mmol) in NMP (2 mL) and the reaction mixture was stirred at 120° C. for 22 h. HPLC purification provided the title compound (0.22 g, 17% yield).
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]
Reactant: S
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 64 h
Yield: 73 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 3.0 g (0.0103 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 10 ml of pyridine and 1.0 ml of triethylamine. The green solution was left to stand for 64 hrs., then degassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 2.45 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-thiocarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:14]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH:19]([C:29](Cl)=O)[C:18]=2[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O>[CH:14]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH:19]([CH2:29][NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1c2ccccc2CCc2ccccc21
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2CNc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A solution of 4.7 grams (50 milliliters) of 4-aminopyridine in 50 c.c. of dry pyridine was treated dropwise at room temperature with a solution of 6.6 grams of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylcarbonyl chloride (M. A. Davis, Stanley O. Winthrop, J. Steward, F. A. Sunahara, and F. Herr, J. Medicin. Chem. 1963, 6, 251-5) in 50 c.c. of toluene. After the exothermic reaction subsided the mixture was stirred at room temperature for 4 hours and was then poured into 30 c.c. of water. 100 milliliters of toluene were added and the phases were separated. The toluene phase was washed once with 100 c.c. of water, then the combined aqueous phases were back-extracted with toluene (3×100 c.c.). The combined toluene solutions were dried (MgSO4) and evaporated, leaving an oily residue which was evaporated several times with further toluene and finally once with ethanol to remove residual pyridine, giving 8.45 grams of a yellow solid. This solid was crystallised from toluene (charcoal) giving off-white crystals (4.78 g. 61%), mp 145°-6°; second crop, off-white crystals (0.96 g, 12%), mp 145°-7.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]#[N:18].[C:19](Cl)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CCOC(C)=O.[Zn]>[C:19]([C:14]1[NH:13][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[C:16]([C:17]#[N:18])[CH:15]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1cc[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)c(-c2cc(C(F)(F)F)ccc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a mixture of 2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (450 mg, 1.66 mmol) in toluene (3 mL) was added acetyl chloride (0.176 mL, 2.49 mmol) at room temperature, under nitrogen, and zinc (217 mg, 3.32 mmol). The mixture was allowed to stir for 3 h at 80° C. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (0 to 10% EtOAc/hexane) to afford the title compound (386 mg, 74%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (3.51 g, 25 mmol) was added dropwise to a solution of 2-chloro-5-methylphenol (3.92 g, 27.5 mmol) and triethylamine (5 mL) in dichloromethane (100 mL), The mixture was stirred for 18 hours at room temperature and concentrated under reduced pressure. Diethylether (200 mL) and water (100 mL) were added. The organic layer was separated and extracted with 2N NaOH (2×100 mL) and brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting colourless oil solidified in the freezer. Yield: 5.82 g (94%). 1H-NMR (400 MHz, CDCl3) δ=2.38 (s, 3H, —CH3), 7.05 (d, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.51-7.56 (m, 2H), 7.64-7.7.70 (m, 1H), 8.22-8.28 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=21.41, 123.97, 124.58, 128.07, 128.85, 129.15, 130.07, 130.55, 134.01, 138.38, 146.98, 164.51.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)=[O:6].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1 g, 3.39 mmol, prepared according to the method of J. Med. Chem., 1997, 40, 1347) in DME (40 mL) was added furan-2-boronic acid (0.455 g, 4.07 mmol), bis(triphenylphosphine) palladium(II)chloride (0.271 g, 0.386 mmol) and saturated NaHCO3 solution (12 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 5 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo . The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the subtitle compound (0.586 g, 61.2% yield).