Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[Br:32]CC.[Br-].[Na+]>O.CC(O)C.CN1CCCC1=O>[Br:32][CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1
Reactant: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(C)O
Product: O=c1c2ccc(CBr)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
10.0 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one, 35 mL of bromoethane and 2.42 g of sodium bromide were added to 80 mL of N-methyl-2-pyrrolidone, and this was stirred for 1.5 hours at 55-60° C. After cooling the reaction mixture, 20 mL of 2-propanol and 50 mL of water were added dropwise and solids were filtered to obtain a white solid. The obtained white solid, 35 mL of bromoethane and 2.42 g of sodium bromide were added to 80 mL of N-methyl-2-pyrrolidone, and this was stirred for 1 hour at 55-60° C. After cooling the reaction mixture, 20 mL of 2-propanol and 50 mL of water were added dropwise and solids were filtered to obtain 9.04 g of 6-(bromomethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one in the form of a white solid.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[NH:11]([C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)[NH2:12]>CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:11]([C:13]3[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:12]=[CH:4][C:3]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1cccc(S(N)(=O)=O)c1
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Temperature: 185 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a 45 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (1.05 g, 4.18 mmol), 3-hydrazinylbenzenesulfonamide (800 mg, 4.27 mmol), and anhydrous NMP (15 mL). The reaction mixture was flushed with argon, securely capped, and heated at 185° C. for 6.5 h. The reaction mixture was cooled to room temperature and slowly added to a rapidly stirred solution of diethyl ether (430 mL). The resulting solid material was filtered and the pale yellow Et2O filtrate was allowed to stand for 18 h at room temperature. The yellow crystals precipitated out and were collected by vacuum filtration to give 425 mg (16.42%) of the title compound as a yellow solid as a “dot” 2 NMP complex by proton NMR. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 400.83. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.56 (s, 2 H) 7.78-7.84 (m, 2 H) 7.89-7.92 (m, 1 H) 8.37-8.42 (m, 2 H) 8.57 (dt, J=4.81, 2.33 Hz, 1 H) 8.75 (s, 1 H). Second and third crops of yellow solid (300 mg, 11.7%; 246 mg, 9.4%) were identical to the first crop of material.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:16][N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1SC(C=C[N+]([O-])=O)=CC=1>C(N)C1C=CC=CC=1>[CH2:18]([N:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)s3)cn(Cc3ccccc3)c2CC1
Agent: O=[N+]([O-])C=Cc1ccc(Cl)s1
Solvent: NCc1ccccc1
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CCNCC3)s1

Procedure:
1-Benzyl-3-(5-chloro-thiophen-2-yl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester. The desired compound (124.5 mg) was prepared from the compound of Example 59, Step B (0.55 g), 280 μL of benzylamine, and 0.49 g of 2-chloro-5-(2-nitro-vinyl)-thiophene as in Example 1, Step A. MS (ESI): exact mass calculated for C24H27ClN2O2S, 442.15; found, m/z 443.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)cccc1O
Product: N#Cc1c(O)cccc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a from 2-amino-6-hydroxybenzonitrile and benzoyl isocyanate as an off-white solid (166 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 6.76 (d, J=8.4 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66-7.73 (m, 2H), 8.04-8.06 (d, J=8 Hz, 2H), 11.24 (s, 1H), 11.30 (s, 1H), 11.42 (s, 1H). MS 281 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[C:30]3[N:29]=[C:28]([CH3:31])[C:27](=[O:32])[NH:26][C:25]=3[N:24]=[CH:23][CH:22]=2)=[CH:18][C:17]=1[F:35]>>[F:35][C:17]1[CH:18]=[C:19]([O:20][C:21]2[C:30]3[N:29]=[C:28]([CH3:31])[C:27](=[O:32])[NH:26][C:25]=3[N:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][C:16]=1[NH:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1nc2c(Oc3ccc(N)c(F)c3)ccnc2[nH]c1=O
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2[nH]c1=O
Yield: 81 %

Procedure:
Method F2 was used with 2-fluoro-5-trifluoromethyl-phenylisocyanate and 8-(4-amino-3-fluorophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one to afford the title compound, yield 81%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]=[C:8]([O:12][CH3:13])[NH:9][C:10]=1[CH3:11])=[O:4].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:7]2[CH:6]([C:14]3[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=3)[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH3:11])[N:9]=[C:8]2[O:12][CH3:13])=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1=C(C)NC(OC)=NC1c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Intermediate 4 (1.56 g, 5.46 mmol) was dissolved in a mixture of DCM (25 mL) and pyridine (10 mL) and cooled using an ice bath. A solution of 4-nitrophenyl chloroformate (705 mg, 3.50 mmol) in DCM (25 mL) was added over 30 minutes. The reaction mixture was stirred for 1 hour at 0° C. and then the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in cyclohexane to gave the title compound as a yellow solid. The product thus obtained was used in the subsequent step without further analysis (2.0 g).
Reaction SMILES: [Si](OCC1C=CC(N)=C(Cl)C=1)(C(C)(C)C)(C)C.C(Cl)(=O)C=C.C(N(CC)C(C)C)C.[Si:31]([O:38][CH2:39][C:40]1[C:45](OC)=[CH:44][C:43]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])=[C:42]([Cl:53])[CH:41]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[Si:31]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])=[C:42]([Cl:53])[CH:41]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: C=CC(=O)Nc1cc(OC)c(CO[Si](C)(C)C(C)(C)C)cc1Cl
Agent: C=CC(=O)Cl
Agent: CC(C)(C)[Si](C)(C)OCc1ccc(N)c(Cl)c1
Agent: CCN(CC)C(C)C
Product: C=CC(=O)Nc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Cl

Procedure:
Obtained as a white crystalline solid (77%) starting from 4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)-2-chloroaniline (intermediate 46; 2 g; 7.36 mmol), acryloyl chloride (0.78 ml; 9.56 mmol) and diethylisopropylamine (1.92 ml, 11.04 mmol) following the experimental procedure as described for intermediate 40.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2I)=[N:4][CH:5]=[CH:6][CH:7]=1>C(NCC)C.CCOCC.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>[Br:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[C:7]#[C:2][CH2:3][CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)c(OCc2ncccc2Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCNCC
Product: CCC#Cc1ccc(Cl)cc1OCc1ncccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.4 %

Procedure:
3-Bromo-2-(5-chloro-2-iodo-phenoxymethyl)-pyridine (3.8 g, 8.9 mmol), is placed in a pressure flask, dissolved in diethylamine:acetonitrile:THF (18 mL:4 mL:4 mL), and degassed with nitrogen for 15 min. An excess of 1-butyne is bubbled through the solution followed by the addition of Cut (507 mg, 2.66 mmol), and PdCl2(PPh3)2 (623 mg, 0.888 mmol). The mixture is stirred at room temperature for 1 h. The mixture is then diluted with ether and washed with saturated aqueous ammonium chloride and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (Biotage® Si65M, 30% hexane/CH2Cl2 then 20% ethyl acetate/hexane) to provide 2.3 g (75%) of the title compound as a pale orange solid. LCMS m/e 351 [M]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[C:8]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(F)ccc(-n2nccn2)c1C(=O)O
Product: Cc1c(F)ccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-2-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][CH2:30]O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[Br:32]Br.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]([Br:32])[CH2:29][CH3:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: BrBr
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCC(Br)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of 3-(3,5-dichlorophenyl)-propanol (200 mg, 0.98 mmol) in CH2Cl2 (20 mL). The reaction mixture was cooled to 0° C. and bromine (207 mg, 1.30 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. The reaction was poured into water and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes) to afford the title compound (134 mg). 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 7.08 (m, 2H), 3.37 (t, 2H), 2.74 (t, 2H), 2.13 (m, 2H).
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:17]([NH:20][NH2:21])(=O)[CH3:18]>CCO>[CH3:18][C:17]1[NH:20][N:21]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: CC(=O)NN
Reactant: CCOC(=N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a suspension of ethyl benzimidate hydrochloride (2.0 g, 10.8 mmol) in EtOH (10 mL) was added sodium ethoxide (3.49 g, 4 mL, 10.8 mmol) at RT. The precipitated NaCl was filtrated off and washed with EtOH (14 mL). The filtrate was charged with acetohydrazide (880 mg, 11.9 mmol) and stirred at RT for 6 d. The crude reaction mixture was concentrated in vacuo. The crude product was suspended in NaOH (1M aqueous solution, 50 mL) and extracted with tert-butyl methyl ether (100 mL). The organic layer was washed with water (50 mL) and the aqueous layers were back-extracted with tert-butyl methyl ether (50 mL). After addition of dry ice to adjust the pH to 7, the organic layer appeared to contain almost no product and was discarded. The aqueous layer was adjusted to pH=7 by addition of HCl (25% aqueous solution) and extracted with dichloromethane (6×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/hexane gradient) as white solid (154 mg, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]12[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:19][C:13]2[O:14][CH2:15][C:16]([F:18])([F:17])[C@:5]3([N:12]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[S:8][CH2:7][CH2:6]3)=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: NC1=N[C@@]2(CCSc3ccc(Br)cc32)C(F)(F)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(Br)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
A solution of (R)-6′-bromo-5,5-difluoro-5,6-dihydro spiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (intermediate B6.9) (460 mg, 1.32 mmol) and triethylamine (267 mg, 2.63 mmol) in dichloromethane (10 ml) was cooled to 0° C. and 4,4′-dimethoxytritylchloride (469 mg, 1.38 mmol) was added. The reaction mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the reaction mixture was evaporated and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=0:100 to 60:40 as the eluent. The (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (789 mg, 92% yield) was obtained as a yellow foam. MS (ISP): m/z=651.0 [M+H]+ and 353.0 [M+2+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1COCC1.[H-].[Na+].CI>CC(C)=O>[CH3:9][N:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]=[N:6]1.[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[N:6]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1cc([N+](=O)[O-])nn1
Product: Cn1nncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %
Yield: 60 %

Procedure:
To a 100-mL single-neck round-bottomed containing 4-nitro-2H-1,2,3-triazole (2.0 g, 17.5 mmol) and THF (10 mL) at 0° C. was added NaH (1.7 g, 35.0 mmol, 2.0 eq.). The mixture was stirred at 0° C. for 15 min. A solution of CH3I (3.68 g, 26.3 mmol, 1.5 eq.) in acetone (40 mL) was added and the resulting reaction mixture was stirred at room temperature for 2 h. After this time, the reaction was quenched by water (20 mL) at 0° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). It was then washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 1-methyl-5-nitro-1H-1,2,3-triazole (1.34 g, 60%) as a white solid and 149a (800 mg, 35%) as a slightly yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 4.26 (s, 3H). 1-Methyl-5-nitro-1H-1,2,3-triazole: 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 4.31 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31]CCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[C:48]1([CH:54]2[CH2:57][CH2:56][N:55]2CC2SC(N3CCC4C(=C(C(=O)/C=C5/SC6C=CC=CC=6N/5COCC[Si](C)(C)C)C=CC=4)C3)=NC=2C(OC)=O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][N:55]3[CH2:56][CH2:57][CH:54]3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/C=C4/Sc5ccccc5N4COCC[Si](C)(C)C)c3C2)sc1CN1CCC1c1ccccc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CN3CCC3c3ccccc3)s1)CC2

Procedure:
The title compound was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 71A: 1H NMR (DMSO-d6): δ 12.89 (s, 1H), 8.04 (d, J=7.36 Hz, 1H), 7.80 (d, J=7.98 Hz, 1H), 7.70 (d, J=7.37 Hz, 1H), 7.34-7.54 (m, 9H), 5.47 (br, 1H), 4.70-4.95 (m, 4H), 4.40 (br, s, 1H), 3.88 (br, 1H), 3.76 (d, J=5.83 Hz, 2H), 2.60-2.8 (br, s, 2H). ESI (+)/MS: 582 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[Cl:10][C:4]1[CH:3]=[C:2]([N:1]([CH2:6][C:5]2[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-2-chlorobenzonitrile (1.0 g, 6.56 mmol, 1 eq) and benzyl bromide (3.12 mL, 26.2 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (1.31 g, 32.8 mmol, 5 eq) portionwise under Ar(g). The reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to yield the product, 2, as a white solid (1.72 g, 79%);
Reaction SMILES: Br[C:2]1[S:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[C:3]=1[CH:19]1[CH2:21][CH2:20]1.[CH3:22]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH:19]1([C:3]2[C:4]3[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=3[S:18][C:2]=2[CH3:22])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(sc(Br)c2C2CC2)C1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1sc2c(c1C1CC1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 76.1 %

Procedure:
A solution of tert-butyl 7-bromo-8-cyclopropyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (264 mg), methylboronic acid (169 mg), potassium phosphate (600 mg), tetrakis(triphenylphosphine)palladium (81.7 mg) and DME (3 mL) was stirred at 80° C. for 20 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→10% ethyl acetate/hexane) to give the title compound (166 mg, 76%) as an oil.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[CH:33][CH:32]=1>CCOCC>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([C@H:37]([OH:43])[CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[CH:33][CH:32]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: CCOCC
Product: C=CCCC[C@@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(+)DIP-Chloride (2.4 g) was dissolved in dry ether (10 mL) and cooled in an ethanol/CO2 bath. 1-(2′,4′-Dichloro-biphenyl-4-yl)-hex-5-en-1-one (1 g) was dissolved in dry ether (5 mL) and added dropwise to the DIP solution. The mixture was allowed to warm to room temperature and stirred for 24 hours. Petrol (50 mL) was added and the organic layer was separated. The aqueous layer was diluted with water and extracted with a further 50 mL petrol. The organics were combined, dried and evaporated to give a thick oil. It was not possible to obtain a pure sample by column chromatography, but no trace of starting material remained, as assessed by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([O:43]COC)[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:15]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1>CO.Cl>[Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:40][CH2:41][CH2:42]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH:15]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN5CCOCC5)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCOCC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
A mixture of 4-(2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (Example 1G) (80 mg, 0.117 mmol) in methanol (1.95 mL) and 10% aqueous HCl solution (0.39 mL) was heated to 65° C. for 3 hours and was then concentrated to dryness. The residue was partitioned between ethyl acetate and saturated aqueous bicarbonate solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound. MS ESI (−) m/z 639.52 [M−H]−.