Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].Cl>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:31]
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolve 5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (7.0 g, 0.026 mol) and triethylamine (4 mL) in dichloromethane (100 mL) and cool with an ice-bath. Add, by dropwise addition, a solution of chloroacetyl chloride (3.23 g, 0.0286 mol) in dichloromethane (25 mL). Stir at room temperature for 12 hours, shake with dilute hydrochloric acid and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]=[O:47])=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]([OH:47])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 0.6 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. A solution of (4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (518, 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to −10° C. over 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (519, 397 mg, 86%). MS (ESI) [M+H+]+=628.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)C>CN(C)C=O>[CH3:18][S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:21][C:19](=[O:22])[CH3:20])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Yield: 98.6 %

Procedure:
A solution of 4′-bromomethyl-3-methylsulfonylbiphenyl (190 mg, 0.57 mmol) (WO 01/70753) and potassium thioacetate (78 mg, 0.68 mmol) in N,N-dimethylformamide (4 mL) was heated at 150° C. in a microwave for 3 min. The reaction mixture was poured into diethyl ether (30 mL) and washed with water (3×15 mL), brine (15 mL), dried with magnesium sulfate, filtered, and concentrated to give a crude yellow oil. The crude oil was purified by flash column chromatography to yield 1.35-A (180 mg, 89%) as a thick light yellow oil. LCMS found for C16H17O3S2 (M+H)+: m/z=321.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[F:65]C1C=CC=CC=1C(NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[F:65])[NH:55][C:56]([O:58][CH3:59])=[O:57])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1F
Yield: 8 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid (0.061 g, 0.269 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-(2-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.012 g, 8%) as a white solid. LCMS-ESI+: calc'd for C47H49FN8O6: 840.38 (M+); Found: 841.86 (M+H+).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[Cs+].O.Cl>CS(C)=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: [F-]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 155 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and cesium fluoride (456 mg, 3.0 mmol) in dry DMSO (1 ml) was stirred for 16 h at 155° C. in a sealed flask. Water (3 ml) was added to the cooled mixture followed by 4M hydrochloric acid to pH <2. The precipitated beige solid was isolated by filtration, washed with water and dried to give 193 mg (80%) of the title compound; 1H-NMR (DMSO-d6): δ7.09 (s, 1H), 7.34 (br s, 1H; MS: m/e 240/242 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:9][C@@H:10]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]>CN(C=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([OH:33])=[O:32])[CH2:9][C@@H:10]([C:21]([OH:23])=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)OCc1ccccc1)N(CCCl)CCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)O)N(CCCl)CCCl)C(=O)O

Procedure:
A solution of the intermediate dibenzyl 4-[N,N-bis(2-chloroethyl)amino]-phenylcarbamoyl-L-glutamate (1.138 g) in DMF (15 ml) was hydrogenated over 10% Pd/C for 16 hours. After filtration and evaporation in vacuo, the residue was dissolved in CHCl3 (20 ml). After 18 hours the crystalline precipitate was filtered off and dried in vacuo to obtain 4-[N,N-bis-(2-chloroethyl)amino]phenylcarbamoyl-L-glutamic acid. Yield, 730 mg (93%). After recrystallisation from acetone/CHCl3 microscopic rods formed m.p. 116°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(O)[CH:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>S(Cl)(Cl)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C(c2ccc(C#N)cc2)n2ccnc2)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=C(c2ccc(C#N)cc2)n2ccnc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2,2-Bis-(4-methoxyphenyl)-2-hydroxy-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethane (10.2 g) is dissolved in thionyl chloride (25 mL) and the solution is stirred at room temperature for 36 hours. The solvent is evaporated and the residue is chromatographed on silica gel (250 g). Elution with ethyl acetate affords the crystalline 2,2-bis-(4-methoxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylene. The compound has m.p. 174°-176° after recrystallization from isopropanol.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][SH:10])=[CH:4][CH:3]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: SCCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(SCCc2ccncc2)cc1

Procedure:
A mixture of 2-(pyridin-4-yl)ethanethiol hydrochloride (3.84 g, 21.8 mmol, 4-fluoro-1-nitrobenzene (6.12 g, 43.3 mmol), and K2CO3 (9.0 g, 65.1 mmol) in acetonitrile (150 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/1) to afford 2.0 g of 4-(2-((4-nitrophenyl)thio)ethyl)pyridine as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, 2H), 8.14 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 3.30 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18][C:17]2=[O:24])=[CH:13][CH:12]=1.OS([O-])(=O)=O.[Na+].O>C1COCC1>[Br:1][CH:18]1[C:19](=[O:23])[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:26][CH:25]=2)[C:17]1=[O:24]
Reactant: COc1ccc(CN2CCCC(=O)CC2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCCC(=O)C(Br)C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 151.7 %

Procedure:
N-Bromosuccinimide (2.88 g, 16.17 mmol) was added portionwise to a stirred solution of 1-(4-methoxy-benzyl)-azepane-2,4-dione (4.0 g, 16.17 mmol) and NaHSO4.H2O (0.67 g, 4.85 mmol) in THF anhydrous (80 mL) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours and the solvent evaporated in vacuo to yield 3-bromodihydro-1-[(4-methoxyphenyl)methyl]-1H-azepine-2,4(3H,5H)-dione (8 g, 91% yield, 60% pure) as a viscous orange oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccccc1
Product: COc1ccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (6-methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[CH2:47][CH2:48][NH2:49]>C1COCC1>[F:42][C:43]([F:53])([F:54])[C:44]1[CH:45]=[C:46]([CH2:47][CH2:48][NH:49][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:32])[CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-trifluoromethylphenethylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC MS(ISP): 614.6 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.[Br:26]N1C(=O)CCC1=O>C1COCC1>[Br:26][C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (32 mg, 0.096 mmol) in THF (0.7 mL) was added N-bromosuccinimide (19 mg, 0.10 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. Purification on silica gel using EtOAc/hexane gave the title compound, 24 mg. LCMS calc. for C19H16BrN4O2 (M+H)+: m/z=411.0, 413.0. found: 411.1, 413.1. 1H NMR (300 MHz, DMSO-d6): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 7.08 (s, 1H); 6.30 (s, 1H); 5.50 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][O:4][C:5]2([CH2:8][CH2:9][CH:10]([O:13][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH2:11][CH2:12]2)[O:6][CH2:7]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC2(CCC(Oc3ccc(C#N)cc3)CC2)OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add dropwise a solution of 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol, (NE4-A05445-029, 1377 mg, 6.88 mmol) in DMF (2.0 mL) to a suspension of sodium hydride (412 mg, 10.32 mmol) in DMF (8.0 mL). Let the reaction mixture stir at room temperature for 1 h, then heat while stirring at 50° C. for 20 minutes (min). Add dropwise a solution of 4-fluoro-benzonitrile (1000 mg, 8.26 mmol) in DMF (4.2 mL). Continue the heating at 60° C. and stirring for 2 hours (h). Concentrate the reaction mixture to remove DMF. Wash the residue with water (15 mL) and extract with EtOAc/hexanes (20 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by flash chromatography (eluent CH2Cl2/hexanes 2/1) to give xxx mg (xx % yield) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(OCC)(=O)C>[CH2:30]([S:32]([N:23]1[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:24]1)(=[O:34])=[O:33])[CH3:31]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of crude 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (16, 423.7 g, 1.03 mol) in ethyl acetate (EtOAc, 6.5 L) at 0-5° C. was added a solution of ethane sulfonyl chloride (EtSO2Cl, 117 mL, 1.23 mol, 1.2 equiv) in ethyl acetate (110 mL) drop wise. The resulting reaction mixture was allowed to warm gradually to room temperature and stirred at room temperature for overnight. When LCMS analysis showed that no starting material remained and the reaction mixture was transferred to a 22 L separation funnel and washed with water (4 L), brine (2 L) and saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L). The combined aqueous layer was back extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude material was purified on silica gel eluted with dichlormethane/ethyl acetate (100/0 to 0/100). The fractions containing the pure desired product (12) were combined and concentrated under reduced pressure to a minimum volume before being treated with heptane at room temperature. The solids were collected by filtration and washed with heptane to afford 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 397 g, 516.7 g theoretical, 76.8% yield) as white solids, which was found to be identical to the material prepared by method A in every comparable aspect. For 12: 1H NMR (CDCl3, 300 MHz), δ 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), −0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:18])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O+](CC)CC)[CH3:20].F[B-](F)(F)F.[H+].ClCCl>C(Cl)(Cl)Cl>[C:1]1([N:7]=[C:8]([O:18][CH2:19][CH3:20])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[O+](CC)CC
Reactant: O=C(C=CSc1ccccc1)Nc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(C=CSc1ccccc1)=Nc1ccccc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-phenyl-3-(phenylthio)acrylamide (2.0 g) was dissolved to chloroform (10 ml), and 7.8 ml of tetrafluoroboric acid triethyloxonium-dichloromethane 1 mol/L solution was added thereto dropwise under ice-cooling. It was stirred for one hour at room temperature, 50° C. for two hours and for five hours under heat refluxing. After cooling, ice-water was added to the reaction solution, then the chloroform layer was separated. The chloroform layer was washed with water, dried and distilled off the solvent. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=15/1) to obtain ethyl N-phenyl-3-(phenylthio)acrylimidate (0.15 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:12][O:13]C(=O)C)[C:5]([CH:21]([CH3:23])[CH3:22])=[C:4]([Cl:24])[N:3]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:5]([CH:21]([CH3:22])[CH3:23])=[C:4]([Cl:24])[N:3]=1
Reactant: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a stirred solution of (4) (5 g, 13.54 mmol) in THF (20 ml) at room temperature, was added lithium hydroxide (649 mg, 27 mmol) followed by distilled water (20 ml). After stirring for 23 hr., THF was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:4 to 1:1)) to afford 2.92 g (66%) of a white solid; m.p. 140-141° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.4 Hz), 1.76 (1H, t, J=5.6 Hz), 2.39 (3H, s), 3.58 (1H, m), 4.69 (2H, d, J=5.6 Hz), 6.84 (1H, s), 6.95 (1H, s), 7.09 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][NH:17][CH3:18]>Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])[CH3:18])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CNCCCN(C)C
Agent: Cl
Product: CN(C)CCCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 2,5-dichloronitrobenzene (3.0 g, 16 mmol) was added N1,N1,N3-trimethylpropane-1,3-diamine (2.2 g, 19 mmol). The mixture was stirred for 2.5 days at RT, diluted with 0.01 N HCl and extracted with EtOAc. The aqueous layer was made basic with Na2CO3 and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to yield 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine as an orange oil. MS m/z=272 [M+H]−. Calc'd for C12H18ClN3O2: 271.75.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:11]2[C:10]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=2)=[CH:9]1)=O)(C)(C)C.C(Cl)Cl.B(Br)(Br)Br>CO>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[NH:8][CH:9]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(O)cc1)c1c[nH]c2ncc(-c3cccs3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (118, 100.0 mg, 0.23 mmol) and methylene chloride (15.0 mL) were combined under an atmosphere of nitrogen. Boron tribromide (1.0 M in methylene chloride, 3.0 mL) was added. The reaction was stirred at room temperature overnight. Methanol (2.0 mL) was added into the the reaction mixture. The reaction was concentrated to remove solvents. The residue was extracted with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography. The product was washed with methanol to provide compound (P-0024, 25.0 mg, 34%). MS(ESI) [M+H+]+=321.