Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](F)[N:8]=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:20]([O:27][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[CH:12]=[CH:11][N:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccnc(OCc3ccccc3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine (2.50 g, 9.50 mmol) prepared in Example 95a and benzyl alcohol (1.97 mL, 19.0 mmol) in DMF (48 mL), sodium hydride (0.90 g, 23.7 mmol) was added, and the reaction solution was stirred at room temperature for 6 hours. To the reaction solution, an aqueous ammonium chloride solution (200 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was washed twice with water (200 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:2) to yield the title compound (3.29 g, 99%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[Br:25]N1C(=O)CCC1=O>Cl.C(O)=O>[Br:25][C:18]1[C:13]2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: Cl
Solvent: O=CO
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Br)c2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
30 g (0.092 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 600 ml of concentrated hydrochloric acid and 600 ml of formic acid, treated with 49.5 g of N-bromosuccinimide and stirred at room temperature for 48 hours. Subsequently, an additional 33 g of N-bromosuccinimide are added thereto and the mixture is stirred at room temperature for 4 days. The solution is evaporated and the residue is poured into ice and aqueous ammonia. After extracting the aqueous solution three times with methylene chloride, the organic phase is dried and evaporated. The residue is chromatographed on 2 kg of silica gel with methylene chloride and methylene chloride/ethyl acetate (20:1) as the elution agent. There is obtained 9-bromo-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 164° (ether/n-hexane).
Reaction SMILES: C(N(CC)CC)C.N1(O)C2C=CC=CC=2N=N1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([OH:30])=O)=[CH:21][CH:20]=1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([NH:43][O:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)=[O:30])=[CH:23][CH:24]=1
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Yield: 76.5 %

Procedure:
Triethylamine (5.49 g, 54.3 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (7.5 g, 49 mmol) were added to a solution of the (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (9.1 g, 27.1 mmol) in dichloromethane (100 mL). After 10 minutes O-tetrahydro-2H-pyran-2yl-hydroxylamine (4.6 g, 39 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (7.2 g, 38 mmol). After 12 h the reaction was quenched by the addition of saturated aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 7:3-6:4) afforded the title compound as a white solid (9.0 g, 76%). LCMS m/z 434.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.90 Hz, 6H) 1.69 (br. s., 3H) 1.78-2.06 (m, 1H) 2.27-2.55 (m, 2H) 2.59-2.72 (m, 1H) 3.03 (d, J=6.64 Hz, 3H) 3.50 (d, J=11.32 Hz, 1H) 3.95-4.22 (m, 1H) 4.97 (d, J=9.37 Hz, 1H) 7.22 (dd, J=8.39, 4.49 Hz, 2H) 7.49 (d, J=8.20 Hz, 2H) 11.36 (br. s., 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:20][C:21](=[O:27])[O:22]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])O)[C:5]([F:8])=[N:6][CH:7]=1.Cl.C(N(CC)C(C)C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[O:27][C:21](=[O:22])[NH:20]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1cc(F)ccc1F
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of optically-enriched tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (380 mg, 0.850 mmol) in dichloromethane (6 mL) at room temperature was added hydrochloric acid (4M in dioxane, 10 mL, 40.0 mmol). The resulting solution was placed in a 45° C. bath. After 20 min, the reaction was concentrated. The resulting viscous oil was dissolved in and reconcentrated from tetrahydrofuran (3×) to give a white solid. The resulting residue was suspended in tetrahydrofuran (15 mL), and treated with diethylisopropylamine (0.297 mL, 1.70 mmol). After stirring briefly, the mixture was cooled to 0° C. and treated with carbonyldiimidazole (207 mg, 1.27 mmol) as a solid in one portion. The ice bath was removed and stirring continued for 1.5 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The material was purified by column chromatography (EtOAc/Hex) to give the product as a mixture of regioisomers. The material was re-purified by chiral prep HPLC (Chiralcel OJ, 30% EtOH/heptane/0.1% DEA) to afford 88 mg (25%). 1H NMR (CDCl3) δ: 8.33 (dd, J=2.3, 1.4 Hz, 1H), 8.11 (dd, J=8.2, 2.1 Hz, 1H), 7.21-7.27 (m, 1H), 7.09-7.17 (m, 2H), 6.48 (br. s., 1H), 5.58 (d, J=5.8 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H). 19F NMR (CDCl3) δ: −74.27 (br. s., 1F), −116.97 (d, J=17.3 Hz, 1F), −123.78-123.41 (m, 1F). Mass spec.: 373.0 (MH)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15]OS(C)(=O)=O)(=O)=O.[S-2:32].[Na+].[Na+]>CS(C)=O>[CH2:14]1[C:13]2[CH:12]=[CH:11][C:10]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][C:8]=2[CH2:7][CH2:6][S:32][CH2:15]1
Reactant: [S-2]
Reactant: CS(=O)(=O)OCCc1ccc(NC(=O)OCc2ccccc2)cc1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc2c(c1)CCSCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a stirred solution of the bis mesylate (from step 4) (5.0 g, 10.6 mmol) in dry DMSO (72 mL) is added anhydrous sodium sulfide (2.48 g, 31.8 mmol). The reaction mixture is stirred at RT for 1 h. The reaction mixture is partitioned between H2O (250 mL) and ethyl acetate (250 mL). The phases are separated, the aqueous phases is extracted with ethyl acetate (3×200 mL). The combined organic phases are dried (MgSO4), filtered and concentrated. The residue is dissolved in CH2Cl2, absorbed onto silica gel and is purified on a Biotage 40M column with SIM using 10-20% ethyl acetate in hexane as the eluent to afford 2.37 g (7.6 mmol, 71%) of the desired product as a white solid. mp 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:24](=[O:26])[CH3:25])[C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C1Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-2-indolinone (6.8 g, 18.9 mmol) in acetic anhydride is heated at reflux temperature with stirring for 30 minutes, cooled to room temperature and concentrated in vacuo to give a brown wet residue. The residue is re-evaporated twice using xylenes and chromatographed using 10% ethyl acetate in hexane to give the title product as a white solid, 5.1 g (67%), mp 119°-121° C., identified by 1HNMR.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][C@@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@@H:23]4[CH3:22])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 92.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (S)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.298 g, 91.2% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Sn](C)(C)C)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(F)(F)F)cc1

Procedure:
A solution of 388 mg (1.52 mmol,1.4 eq.) of 4-methylphenyltrimethylstannane (Example 69, Step A) in 5 mL of toluene under a nitrogen atmosphere was treated with 238 mg of 2-bromobenzotrifluoride (1.06 mmol) and 64 mg of tetrakis(triphenylphosphine) palladium(0) and the resulting solution heated at reflux for 14 hours. The mixture was cooled, filtered and concentrated under vacuum to give an amber oil that was chromatographed on silica, eluting with hexane, to give the product. 1H NMR (300 MHz,CDCl3): 2.41 (s,3H), 7.2-7.8 (m,8H). EI-MS: calculated for C14H11F3 236; found 236 (M+,100%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(O)C.O>[CH2:12]([NH:30][CH:11]1[O:4][C@@H:3]([CH3:2])[C@H:5]([OH:6])[C@@H:7]([OH:8])[C@H:9]1[OH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 50 h

Procedure:
9 g of L-rhamnose and 13.5 g of stearylamine in 100 ml of 2-propanol and 50 ml of water are stirred at 50° C. until a clear solution has resulted. After 50 hours at room temperature, the crystals are filtered off with suction, washed with ethanol and ether and dried in vacuo.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Yield: 78.6 %

Procedure:
1-((1,1′-Biphenyl)-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (1030 mg, 3.3 mmol) is alkylated by treating with 0.31 mL (3.3 mmol) of methyl bromoacetate and 132 mg (3.3 mmol) and 132 mg (3.3 mmol) of 60% NaH/mineral oil in DMF and stirring maintained for about 17 hours. The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4), and concentrated at reduced pressure. The product is purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1000 mg (79% yield) of ((1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid methyl ester; mp 99°-102° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:17]([CH2:18][CH2:19]O)=[CH:16][C:15]2[NH:14][C:13](=[O:21])[CH:12]3[CH2:22][CH2:23][CH2:24][CH:11]3[C:10]=2[CH:9]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CS(C)=O.ClCCl.C(OCC)(=O)C.C1COCC1>[Cl:7][C:8]1[C:17]([CH2:18][CH2:19][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=2)=[CH:16][C:15]2[NH:14][C:13](=[O:21])[CH:12]3[CH2:22][CH2:23][CH2:24][CH:11]3[C:10]=2[CH:9]=1
Reactant: O=C1Nc2cc(CCO)c(Cl)cc2C2CCCC12
Reactant: NCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCNCc3cccc(Cl)c3)c(Cl)cc2C2CCCC12
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 55.4 %

Procedure:
0.22 ml (3.12 mmol) of DMSO in 2 ml of 1,2-dichlorethane is added in drops to a solution of 0.18 ml (2.04 mmol) of oxalyl chloride in 4 ml of 1,2-dichloroethane at −70° C. After 10 minutes at −70° C., a solution of 270 mg (1.02 mmol) of 8-chloro-7-hydroxyethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 5 ml of 1,2-dichloroethane and 2 ml of DMSO are added in drops to it. After 2 hours at −70° C., the batch is diluted with 30 ml of dichloromethane and stirred for 3 hours at −70° C. After 1.27 ml (9.18 mmol) of triethylamine is added, the reaction solution is stirred for 1 hour at room temperature and concentrated by evaporation in a vacuum. The residue is taken up in 20 ml of 1,2-dichloroethane and 20 ml of THF and mixed with 0.14 ml (1.53 mmol) of 3-chlorobenzylamine, 323 mg (1.53 mmol) of sodium (triacetoxy)borohydride and 0.6 ml (10.2 mmol) of acetic acid. After 24 hours at room temperature, the batch is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with dichloromethane-methanol yields 220 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([C:12]3(O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[O:9][C:8]=12.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:15]1[CH2:14][CH:13]=[C:12]([C:10]2[O:9][C:8]3=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]3[CH:11]=2)[CH2:17][CH2:16]1
Reactant: COc1nccc2cc(C3(O)CCOCC3)oc12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nccc2cc(C3=CCOCC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
A solution of 4-(7-methoxyfuro[2,3-c]pyridin-2-yl)tetrahydopyran-4-ol (2.5 g) in dry dichloromethane (50 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Triethylamine (5.6 ml) was added followed by methanesulfonyl chloride (2.3 ml). The mixture was stirred overnight at room temperature. The solvent was removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave 2-(3,6-dihydro-2H-pyran-4-yl)-7-methoxyfuro[2,3-c]pyridine (2.5 g) as a colourless oil.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1
Agent: Cl
Product: Clc1cc2c(cc1N1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-chloro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 241.4 ({37Cl}M+H+, 52%), 239.3 ({35Cl}M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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>[Si:10]([O:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:17]#[N:18])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)ccn1
Temperature: 95 °C
Yield: 26 %

Procedure:
To a stirring solution of 4-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyridine INT-70 (0.800 g, 2.6 mmol) in 3 mL of 1-methyl-2-pyrrolidine (NMP) was added zinc cyanide (0.610 g, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol). The solution was degassed with N2 and the reaction mixture heated at 95° C. for 12 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (MeOH/DCM) to produce 0.170 g (26%) of 2-((tert-butyldimethylsilyloxy)methyl)isonicotinonitrile INT-71 as a light yellow solid. LCMS-ESI (m/z) calculated for C13H20N2OSi: 248.4; found 249.1 [M+H]+, tR=4.21 min (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of DMAP (0.012 g, 0.096 mmol), 5-bromo-2-chloropyridin-3-amine (0.2 g, 0.96 mmol) and benzene sulfonyl chloride (0.61 ml, 4.8 mmol) in pyridine (0.16 ml, 1.92 mmol) is heated at 50° C. overnight. The reaction is cooled to room temperature and absorbed onto silica. Purification by flash chromatography (SiO2, 10-20% EtOAc in iso-hexane) yields N-(5-Bromo-2-chloro-pyridin-3-yl)-benzenesulfonamide as a white solid. [M+H]+ 347.
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][C:7]1[CH-:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[C:12]([CH3:24])=[CH:11][CH:10]=2.[Li+]>C1COCC1>[CH3:3][Si:2]([CH3:4])([CH:8]1[C:9]2[C:14](=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=3)[C:12]([CH3:24])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH3:6])[CH:8]1[C:9]2[C:14](=[C:13]([C:16]3[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=3)[C:12]([CH3:24])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH3:6]
Reactant: Cc1cc(C)cc(-c2c(C)ccc3[cH-]c(C)cc23)c1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=Cc2c(ccc(C)c2-c2cc(C)cc(C)c2)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2-c1cc(C)cc(C)c1
Yield: 99.2 %

Procedure:
Dichlorodimethylsilane (0.40 g, 3.1 mmol) was dissolved in 40 ml of THF. While stirring, lithium[2,5-dimethyl-4-(3,5-dimethylphenyl)indenide] (1.6 g, 6.2 mmol), prepared as described under (g) above, was added as a dry powder and the resultant mixture was stirred overnight at room temperature. Thereafter the solvent was removed in vacuo and the residue was taken up in pentane and filtered to remove LiCl. The pentane was removed in vacuo to yield a flaky white solid (1.7 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(OC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-methoxyphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.43 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[C:29]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[CH3:45])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:42]2[CH2:43][CH2:44][N:39]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH:40]([CH3:45])[CH2:41]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC1CNCCN1C(=O)OCc1ccccc1
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1C(=O)OCc1ccccc1

Procedure:
The benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-2-methylpiperazine-1-carboxylate was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (INTERMEDIATE AAA1) and 1-CBz-2-methylpiperazine as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): δ 1.08 (d, 3H, J=5.9 Hz), 2.00 (m, 1H), 2.10 (m, 1H), 2.52 (d, 1H, J=11.0 Hz), 2.70 (m, 1H), 3.06 (m, 1H), 3.26 (m, 1H), 3.46 (m, 1H), 3.86 (d, 1H, J=12.5 Hz), 4.24.5 (m, 3H), 5.05 (s, 1H), 5.14 (abq, 2H, J=12.4 Hz), 6.25 (d, 1H, J=13.3 Hz), 6.82 (s, 1H), 7.30-7.60 (m, 12H). MS (API-ES+): 651 (M+H).