Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9](=[O:23])[NH:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:25]([C@H:27]4[CH2:31][N:30]([C@@H:32]([C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[CH3:33])[C:29](=[O:42])[CH2:28]4)[CH3:26])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: COc1ccc(-c2cc3ncn(C4CC4)c3c(=O)[nH]2)cc1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C5CC5)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4 (5H)-one 2.37 (48.9 mg, 0.157 mmol), lactam alcohol 1.05 (63 mg, 0.24 mmol), and PPh3 (63 mg, 0.24 mmol) were taken up in THF (1.6 mL). To the resulting suspension was added DEAD (38 μL, 0.24 mmol) dropwise. The resulting mixture was heated to 40° C. and stirred 15 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography (35% to 55% to 65% to 100% acetone in hexanes) gave (R)-4-((R)-1-(3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17].[C:20]1([NH2:27])[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1>ClCCl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][S:16]([C:4]1[CH:5]=[C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:18])=[O:17]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 2-methoxy-5-trifluoromethanesulfonyl-1-benzenesulfonyl chloride (5 g) in dry dichloromethane (10 mL), benzene-1,2-diamine (5 g) was added followed by addition of dry pyridine (10 mL) at 0° C. The resulting deep red reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (250 mL). The contents were washed with saturated aqueous sodium chloride solution (50 mL) and saturated aqueous sodium carbonate solution (50 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc (7:1 to 4:1) to give N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (6 g). LC: Tr 0.95 min, MS: 411 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.18 (bs, 2H), 4.21 (s, 3H), 6.43 (m, 2H), 6.57 (bs, 1H), 6.75 (dd, 1H), 7.02 (t, 1H), 7.35 (d, 1H), 8.22 (dd, 1H), 8.40 (d, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C1(SC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CSc1ccccc1
Solvent: ClCCCl
Product: O=Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
3-nitrobenzoylchloride (5.0 g, 26.94 mmol) was added to a solution of thioanisole (3.16 ml, 26.94 mmol) and 1,2-dichlorethane (95 mL). The resulting reaction mixture was cooled to 0° C. (ice/H2O bath) and 0.5 equivalents of aluminum trichloride (1.8 g, 13.47 mmol) was added. The reaction was allowed to stir for 15 min at this temperature and the cold bath was removed followed by addition of the remaining equivalents of AlCl3 (2.51 g, 18.87). The reaction solution turned a dark greenish/yellow and was allowed to stir at room temp. for 18 h, after which time the reaction was quenched slowly with H2O (50 mL). The mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (3×50 mL), and the combined organic phases were washed with satd NaHCO3 (50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc/hexane, ¼) to afford 3.3 g (44%) of 4-(methylsulfanyl)phenyl](3-nitrophenyl)methanone as a solid. EI-LRMS m/z 274 (M+); TLC Rf 0.68 (EtOAc/Hex, ⅔). Step 2. Preparation of (3-aminophenyl)[4-(methylsulfanyl)phenyl]methanone
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.6 g), triethylamine (1.8 cc) and 4- (1,2-benzisoxazol-3-yl)piperazine (2.69) in dimethylformamide (200 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 263° C.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]=1
Reactant: COCOc1cc(OCc2ccccc2)c(C(C)C)cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COCOc1cc(O)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude methyl 4-benzyloxy-5-isopropyl-2-(methoxymethyloxy)benzoate was dissolved in methanol (20 ml), 10% palladium on carbon (160 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the catalyst was rinsed with methanol (3×5 ml) and the combined filtrates were evaporated in vacuo to afford crude methyl 4-hydroxy-5-isopropyl-2-(methoxymethyloxy)benzoate as a colourless oily solid that was used in the next step without further purification. 1H NMR (DMSO-d6) 10.19 (1H, br s), 7.52 (1H, s), 6.57 (1H, s), 5.13 (2H, s), 3.73 (3H, s), 3.40 (3H, s), 3.11 (1H, m), 1.13 (6H, d). MS: [M−H]− 253.
Reaction SMILES: Cl.Cl[CH2:3][CH:4]([OH:23])[CH2:5][NH:6][C@@H:7]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].C([O-])(O)=O.[Na+].C(C1OC1)Br>C(O)(C)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:7]([N:6]2[CH2:5][CH:4]([OH:23])[CH2:3]2)[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:17][CH:18]=1
Reactant: N#Cc1cccc([C@@H](NCC(O)CCl)c2ccc(Cl)cc2)c1
Agent: BrCC1CO1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Product: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)c1

Procedure:
To a mixture of 20.27 g (72.6 mmole) of 3-[(S)-[(3-chloro-2-hydroxypropyl)amino](4-chlorophenyl)methyl]benzonitrile hydrochloride and 21.3 g (245 mmole) of NaHCO3 in 600 mL of isopropanol was added 14.4 mL (174 mmole) of epibromohydrin . The mixture was heated to reflux for 24 h, then was cooled and concentrated. The residue was partitioned between 750 mL portions of ether and water and the aqueous layer was washed with two 500 mL portions of ether. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography using 10-20% ethyl acetate in hexane to afford the title compound as a clear oil; 1H-NMR(CDCl3) δ 1.6 (s, 2H, br), 5.24 (s, 1H), 7.24-7.78 (m, 8H).2.89 (m, 2H), 3.54 (m, 2H), 4.39 (s, 1H), 4.52 (m, 1H), 7.2-7.8 (m, 8H).
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][N:21]([CH3:28])[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 2 h
Yield: 89 %

Procedure:
Morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate (non-HCl salt of Example 10; 1.00 g, 3.27 mmol) and 37% formaldehyde in water (1.97 g, 1.82 mL, 65.5 mmol) were dissolved in MeOH (20 mL) at room temperature followed by addition of sodium triacetoxyborohydride (2.78 g, 13.1 mmol) portionwise over 5 minutes. The reaction mixture was stirred for 2 h. The reaction mixture was quenched by the addition of saturated aq Na2CO3 solution. The solvents were removed in vacuo and the residual aqueous phase was loaded onto an Isolute HM-N 20 mL cartridge. The desired product was eluted with DCM (200 mL) and the solvent removed in vacuo to give (4-methylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate (0.93 g, 88.9%) as a colourless gum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COCCOc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of methyl 3-cyano-5-(2-methoxyethoxy)benzoate (375 mg, 1.6 mmol) in tetrahydrofuran (4 mL) was treated with 0.5 N lithium hydroxide (3.8 mL, 1.9 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH˜2. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 343 mg (97%) of 3-cyano-5-(2-methoxyethoxy)benzoic acid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCC(O)CCCCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCC(Br)CCCCC
Yield: 86 %

Procedure:
The title compound (13.87 g) was prepared from Pentadecan-6-ol (Example 11, 12.65 g), carbon tetrabromide (22 g), triphenylphosphine (24.82 g) and dichloromethane (200 ml) using the procedure of Example 6.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.N1C(C)=CC=CC=1C.[Br:24][C:25]1[CH:26]=[C:27]([CH2:31]O)[CH:28]=[N:29][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:26]=1
Reactant: OCc1cncc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (1.174 ml, 5.11 mmol) was added to 2,6-lutidine (0.743 ml, 6.38 mmol) and (5-bromopyridin-3-yl)methanol (800 mg, 4.25 mmol) stirred in CH2Cl2 (10 ml) cooled to 0° C. and the mixture was stirred at 0° C. for 1 h. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to provide 3-bromo-5-({[tertbutyl(dimethyl)silyl]oxy}methyl)pyridine: MS: cal'd 325 (MNa+), exp 325 (MNa+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1[C:20]#[N:21])([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>>[C:1]([O:4][CH2:5][C:6]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[C:20]#[N:21])([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CCC(CC)(COC(C)=O)COc1cccc(N)c1C#N
Product: CCC(CC)(COC(C)=O)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215a from 2-((3-amino-2-cyanophenoxy)methyl)-2-ethylbutyl acetate (Example 232b) and sulfamoyl chloride in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (t, J=7.6 Hz, 6H), 1.37-1.43 (m, 4H), 1.98 (s, 3H), 3.87 (s, 2H), 3.96 (s, 2H), 6.98 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.54 (t, J=8.4 Hz, 1H), 9.46 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[NH4+:14]>CN(C)C=O>[CH:7]1[C:6]([C:10]([NH2:14])=[O:12])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8.06 gm (50 mmol) indole-5-carboxylic acid in 150 ml dimethylformamide were added 8.11 gm (50 mmol) carbonylidiimidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 ml concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oil which was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oil which crystallizes upon standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=4[O:30][CH2:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:38])[CH:3]=1.[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:45][S:42]([CH:39]4[CH2:41][CH2:40]4)(=[O:44])=[O:43])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=4[O:30][CH2:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:38])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CC2)COc2c(F)cccc23)cnc2c(C(=O)O)cnn12
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CC2)COc2c(F)cccc23)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 53.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.079 g, 0.152 mmol) obtained in step 2 and cyclopropanesulfonamide (0.092 g, 0.760 mmol), the title compound (0.051 g, 64%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([NH:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[CH:34]=[C:33]1[CH:41]=O)[CH3:31].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]3[N:24]([CH3:25])[C:41]([C:33]4[N:32]([CH2:30][CH3:31])[C:36]5=[N:37][CH:38]=[CH:39][CH:40]=[C:35]5[CH:34]=4)=[N:21][C:19]=3[CH:20]=2)=[O:28])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1c(C=O)cc2cccnc21
Reactant: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(OC)c3n2C)cc2cccnc21
Temperature: 100 °C
Yield: 75 %

Procedure:
To a solution of (R)-tert-butyl(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (4.5 g, 11.02 mmol) and 1-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.015 g, 11.57 mmol) in ethanol (100 mL) was added portionwise a solution of sodium dithionite (4.25 g, 20.75 mmol) in water (50 mL). The mixture was flushed with nitrogen then heated at 100° C. overnight (16 hours). The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were combined and back washed with water (3×150 ml), collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield 5.5 g of crude product as white solid. The crude product was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a SNAP 100 g silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated in vacuo to afford the title compound as a white solid (4.40 g).
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2>CO>[Cl:3][C:4]1[CH:13]=[C:12]([I:1])[C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2
Reactant: ClI
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Solvent: CO
Product: Cc1ccc2c(Cl)cc(I)c(O)c2n1
Reaction time: 3 h
Yield: 88 %

Procedure:
Iodine monochloride (19.0 g) is added to a solution of 5-chloro-8-hydroxy-2-methylquinoline (21.5 g) in 250 mL of MeOH, and the resulting mixture is stirred for 3 h. Additional iodine monochloride (4.5 g) is then added, and the mixture is stirred for another 18 h. The reaction mixture is quenched with sat'd Na2SO3 (aq), then neutralized with sat'd NaHCO3 (aq). The solid precipitate is collected by filtration and dried under vacuum to give 31.22 g of the title compound as a pale green solid.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:53][C:54]1[CH:55]=[C:56]([CH:60]([NH2:62])[CH3:61])[CH:57]=[CH:58][CH:59]=1.C1(C2SC(C(N)C)=CC=2)C=CC=CC=1.[Cl:77][C:78]1[CH:94]=[CH:93][C:81]2[CH2:82][CH2:83][N:84]([C:87](=[O:92])[C:88]([F:91])([F:90])[F:89])[CH2:85][CH2:86][C:80]=2[C:79]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:77][C:78]1[CH:94]=[CH:93][C:81]2[CH2:82][CH2:83][N:84]([C:87](=[O:92])[C:88]([F:89])([F:91])[F:90])[CH2:85][CH2:86][C:80]=2[C:79]=1[NH:62][CH:60]([C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=1)[CH3:61]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1cccc(F)c1
Agent: [Pd]
Agent: CC(N)c1ccc(-c2ccccc2)s1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccc(F)c1
Temperature: 95 °C
Yield: 78 %

Procedure:
Add tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.8 mmol), BINAP (4.7 g, 7.5 mmol), cesium carbonate (8.6 g, 26.3 mmol) and 1-(3-fluorophenyl)-ethylamine Isomer 2 (5.8 g, 41.3 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (8.0 g, 18.8 mmol) in toluene (225 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95° C. for 8 h. Add additional tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.), and BINAP (0.2 equiv.). Continue heating the reaction for an additional 16 h. Cool the mixture, dilute with EtOAc (200 mL) then filter thru Celite®. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) followed by SCX chromatography to obtain 7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (6.0 g, 78%). GC-MS m/z: 414 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH2:16][C:17](N)=[O:18]>O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:17]([NH2:16])=[O:18])=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(CCCNCCO)cc1
Reactant: NC(N)=O
Solvent: O
Product: N#Cc1ccc(CCCN(CCO)C(N)=O)cc1
Temperature: 130 °C
Yield: 72.7 %

Procedure:
4-[3-(2-Hydroxyethylamino)propyl]benzonitrile (6.7 g, 0.0328 mol; see Preparation A(v) above) and urea (2 g, 0.0328 mol) were mixed and heated at 130° C. for 2 h. The reaction mixture was cooled to room temperature and water was added. The resulting solid was filtered and dried to give 5.9 g (72%) of the sub-title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:36]C(OC(C)(C)C)=O)[C:26]([C:44]([F:47])([F:46])[F:45])=[CH:25][CH:24]=1>>[C:32]([O:31][C:29]([C:28]1[C:27]([OH:36])=[C:26]([C:44]([F:46])([F:47])[F:45])[CH:25]=[CH:24][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[CH:6][CH:7]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: Cc1cc(C(C)C(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 53 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl)propanoate (224 mg, 0.83 mmol) obtained in Example (107-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (415 mg, 0.91 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (235 mg, three-step total yield: 53%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.