Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:17][S@](C(C)(C)C)=O)[CH2:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:34]([O:38][C:39](O[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])([CH3:37])([CH3:36])[CH3:35]>CO.C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH2:24][OH:25])[C@@H:10]([NH:17][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3].[Si:1]([O:8][C@H:9]([CH2:24][OH:25])[C@@H:10]([NH:17][C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[CH2:11][C@@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](=O)N[C@@H](CC1CCOC1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C[C@@H]1CCOC1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H]1CCOC1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution of (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(tetrahydrofuran-3-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (1.5 g, 3.0 mmol) in dry MeOH (30 mL) was brought to −20° C. followed by the addition of 10% HCl (100 mL, MeOH/acetyl chloride) and the resulting mixture was stirred at −20 C for 1 h. The mixture was quenched with 10% Na2CO3 and extracted with DCM (8×). The combined organics were dried over Na2CO4, filtered, concentrated and colorless oil obtained was dissolved in DCM (30 mL) followed by the addition of TEA (1.2 mL, 8.9 mmol) and di-tert-butyldicarbonate (1.0 mL, 4.4 mmol). The reaction was stirred at RT for 17 h. The mixture was concentrated and chromatographed on silica gel using 4:1 to 1:1 EtOAc/hexanes to afford a colorless oil as tert-butyl(2S,3S)-3(tert-butyldimethylsilyloxy)-4-hydroxy-1-((S)-tetrahydrofuran-3-yl)butan-2-ylcarbamate AND Tert-butyl(2S,3S)-3 (tert-butyldimethylsilyloxy)-4-hydroxy-1-((R)-tetrahydrofuran-3-yl)butan-2-ylcarbamate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.CO.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>N1C=CC=CC=1.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[N:24][NH:25][C:26]([NH2:28])=[O:27])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CC(C=NNC(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
To a solution of 0.288 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal in 3 ml. of methanol is added a solution of 0.111 g. of semicarbazide hydrochloride in 0.5 ml. of water, followed by 1 drop of pyridine. The mixture is refluxed briefly and then poured into water. The product is extracted with ethyl acetate and the extract washed, dried and evaporated to afford, upon crystallization from ethyl acetate/hexane, 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal semicarbazone.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[O-:13][CH2:14][CH3:15].[Na+].C(O)C.O.Cl>C(O)C>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:13][CH2:14][CH3:15])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1CBr
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCc1oc(Br)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (4.5 g) in ethanol (50 mL) was added 20% sodium ethoxide-ethanol solution (7.8 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr and at room temperature overnight. The reaction was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (2.8 g, 67%) as an oil.
Reaction SMILES: [Cl-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:8][C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Reactant: Sc1nccs1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To sodium chloride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added 1,3-thiazole-2-thiol (315 mg) at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (2 ml) and the reaction mixture was warmed up to room temperature overnight, then heated at 50° C. for 3 hours. Aqueous work-up and purification on silica yielded 4-(thiazol-2-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (174 mg).
Reaction SMILES: Cl.CN.[CH:4]([N:7](C(C)C)CC)(C)C.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1.C(OCC)(=O)C>CO>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:24])[CH2:25][NH:7][CH3:4])[CH:20]=[CH:21][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCOc1cccc(C2CO2)c1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(O)c1cccc(OCOC)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
Methylamine hydrochloride (275 mg, 4.08 mmol) and diisopropylethylamine (601 mg, 4.66 mmol) were sequentially added to a solution of 2-(3-methoxymethoxy-phenyl)-oxirane (210 mg, 1.16 mmol) in anhydrous methanol (5 mL). The resulting mixture was maintained at ambient temperature for about 12 hours. Following standard extractive workup with ethyl acetate, the crude product was purified by flash column chromatography on silica gel (1×15 cm, dichloromethane/methanol/NH4OH=90/8/1 elution) to give the title product (49 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.26-7.23 (m, 1H), 7.06 (s, 1H), 7.00 (d, 1H, J=7.5 Hz), 6.95 (d, 1H, J=6.9 Hz), 5.18 (s, 2H), 4.71 (d, 1H, J=5.7 Hz), 3.48 (s, 3H), 2.84-2.62 (m, 2H), 2.46 (s, 3H); LC-MS: m/z=212 (MH)+.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)(=[O:30])=[O:29])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccn2)CC1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
Pyridine (1.85 ml) was added to a stirred solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (4.46 g) and pyridine-2-sulphonyl chloride (3.7 g) in dichloromethane (110 ml) at -10° C. under a nitrogen atmosphere. The reaction was then warmed to ambient temperature over 16 hours and poured into water (300 ml). The organic layer was separated and further washed with hydrochloric acid (1 M, 2×200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and brine (200 ml). After drying over anhydrous magnesium sulphate, the solution was evaporated to dryness to afford N-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide (3.5 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].F[C:8]1[C:13]([CH3:14])=[C:12]([I:15])[C:11]([CH3:16])=[CH:10][N:9]=1.CC(OC)(C)C>C1COCC1.O>[I:15][C:12]1[C:11]([CH3:16])=[CH:10][N:9]=[C:8]([O:6][CH:4]([CH3:5])[CH3:3])[C:13]=1[CH3:14]
Reactant: Cc1cnc(F)c(C)c1I
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cnc(OC(C)C)c(C)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil dispersion, 191 mg) was added to a solution of IPA (0.77 mL) in THF (5 mL). After foaming was stopped, a solution of 2-fluoro-4-iodo-3,5-dimethylpyridine obtained in Preparation Example 29 (500 mg) in THF (5 mL) was added to the solution, and the mixture was stirred at mom temperature for two hours. The mixture was stirred at 50° C. for two hours, and the reaction mixture was then cooled to room temperature. The reaction mixture was cooled at 0° C., and MTBE (20 mL) and water (20 mL) were then added. The organic layer was separated. The organic layer was washed with brine. The combined aqueous layers were extracted with MTBE. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (490 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:36]>C(#N)C.C(OCC)(=O)C>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][Br:36])([O-:22])=[O:21]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of triphenylphosphine (2.83 g, 0.011 mol) in 100 mL of acetonitrile was added a solution of 5-nitro-3-(2-hydroxyethyl)indole (2.00 g, 0.0097 mol) in 25 mL of acetonitrile, followed by a solution of CBr4 (3.60 g, 0.011 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 18 h and then another 0.283 g (1.1 mmol) of triphenylphosphine and 0.360 g (1.1 mmol) of CBr4 were added. After 2.5 h the mixture was diluted with ethyl acetate, washed (H2O, brine), dried (Na2SO4) and evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane, 1:4) to give the title compound (2.27 g, 87%) as a yellow solid: IR (neat) 3370, 1334 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.69 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 7.98 (dd, J=9.0, 2.2 Hz, 1H), 7.54-7.49 (m, 2H), 3.76 (t, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH2:32]([O:36][C:37]1([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:33][CH2:34][CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:32]([O:36][C:37]1([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:38][CH2:39][N:40]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:41][CH2:42]1)[CH2:33][CH2:34][CH3:35]
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Reactant: CCCCOC1(C2CCCCC2)CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(C2CCCCC2)CCN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To 69 mg (0.21 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 2 mL of DMF is added a solution of 71 mg (0.20 mmol) of 4-butoxy-4-cyclohexylpiperidine trifluoroacetate in 1.5 mL of DMF, 44 mg (0.23 mmol) of EDC and 33 mg (0.24 mmol) of HOBt. After 2 hours 30 minutes, the reaction medium is hydrolysed with aqueous 2% citric acid solution and then extracted with dichloromethane. The organic phase is then washed with aqueous 1N sodium hydroxide solution. The organic phase is dried over MgSO4, filtered and concentrated. This oil is chromatographed on silica gel (eluent: 8/2 DCM/MeOH). 25 mg of 1-[2-(4-butoxy-4-cyclohexylpiperidin-1-yl)-1-(4-methoxy-benzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea are obtained in a yield of 22%.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>CCOC(C)=O>[OH:9][C:10]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Pyridine hydrochloride (100 g; 0.87 mol) and 2-methoxy-4-nitro-benzonitrile (17 g; ca 96 mmol) was heated to 200° C. for 2 hours, cooled to room temperature and carefully added H2O and EtOAc. The slurry was stirred until all solid dissolved. The organic layer was isolated, washed twice with H2O, brine then dried, filtered and evaporated to dryness to yield 15 g (95%) pure product
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[F:36][CH:37]([F:47])[C:38]1[S:42][C:41](S(N)(=O)=O)=[CH:40][CH:39]=1>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:41]3[S:42][C:38]([CH:37]([F:47])[F:36])=[CH:39][CH:40]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: NS(=O)(=O)c1ccc(C(F)F)s1
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Product: Nc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(C(F)F)s4)cc3)c(=O)c2cc1F

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-difluoromethyl-thiophene-2-sulfonic acid amide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-5-difluoromethylthiophene-2-sulfonamide. ES-MS (M+H)+=523.1; 1H-NMR (DMSO-d6) δ (ppm): 8.70-8.64 (s, 1H), 7.66-7.60 (d, J=12.4 Hz), 7.56-7.48 (m, 2h), 7.38-7.10 (t, J=55.3 Hz, 1H), 7.36-7.32 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.18 (d, J=7.7 Hz, 1H), 7.12-7.06 (m, 2H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.52-6.46 (bs, 1H), 6.48-6.44 (d, J=7.3 Hz, 1H), 2.81-2.77 (bd, J=4.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[C:27]([O:42][CH3:43])=[N:28][C:29]([O:40][CH3:41])=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[C:29]([O:40][CH3:41])=[N:28][C:27]([O:42][CH3:43])=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)c(OC)nc(OC)c4Cl)c(=O)n(C)c3n2)cc1
Yield: 51.4 %

Procedure:
A mixture of 0.66 g (2 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]phenyl]amino]-4-(methylamino)pyrimidine, 1.23 g (4 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate, and 1 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup as in 6 above gives 0.59 g (51%) of the title compound (Compound 21): mp (EtOH) 239–240° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[C:28]([F:30])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([C:19]3[N:24]=[C:23]([NH2:25])[C:22]([O:26][CH3:27])=[CH:21][N:20]=3)=[N:10]2)=[C:6]([F:31])[CH:5]=1)[CH3:2].Cl.F[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:31])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([C:19]3[N:24]=[C:23]([NH:25][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[C:22]([O:26][CH3:27])=[CH:21][N:20]=3)=[N:10]2)=[C:28]([F:30])[CH:29]=1)[CH3:2]
Reactant: Fc1ccncc1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3c(C)cccc32)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3c(C)cccc32)c(F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-4-6, 0.236 mmol, 1.0 eq.) and 94.2 mg 4-Fluoropyridin hydrochloride (0.705 mmol, 3.0 eq.) were dissolved in 1.1 ml of dry N,N-dimethylformamide. 113 mg sodium hydride (60%, 2.82 mmol, 12 eq.) were added. The reaction mixture was stirred at 90° C. for 2 h. Water and ethyl acetate were added and the aqueous layer was washed with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuum. The residue was purified by HPLC to yield 46 mg (0.09 mmol, 38%) of the analytically pure target compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([CH3:26])=[O:25])[CH:19]=[CH:20][C:21]=1[OH:22].O>CN(C=O)C>[CH2:7]([O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:23][C:24]([CH3:26])=[O:25])=[CH:17][C:16]=1[Br:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (2.7 g) and benzyl bromide (2.3 ml) were added to a solution of 1-(3-bromo-4-hydroxyphenyl) acetone (4.0 g) in DMF (40 ml) and the mixture was stirred at room temperature for six hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-[4-(benzyloxy)-3-bromophenyl]acetone (3.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:34])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1.O>CS(C)=O>[ClH:17].[ClH:17].[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:18][CH2:19][CH2:20][N:21]([CH3:34])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: Cl
Reaction time: 0.17 h

Procedure:
1.1 gm (5.0 mmols) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one were suspended in 20 ml of dimethyl sulfoxide, and the suspension was mixed with 0.6 gm (5.3 mmols) of potassium tert. butylate while stirring. After 10 minutes, the solution was mixed with 2.0 gm (7.4 mmols) of 1-chloro-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane; the mixture was stirred for one hour at 50° C. and then poured into water; the aqueous mixture was extracted with ethyl acetate, and the organic phase was evaporated in vacuo. The residue was purified on silica gel with methylene chloride +10% of methanol as the eluant, and the dihydrochloride was precipitated from acetone with ethereal hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].[Cl-].[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:12])=[O:13]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CO
Agent: [Cl-]
Product: COC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
A round bottom flask was charged with 4-chloro-3-(chlorosulfonyl)benzoic acid (16.0 g, 63.24 mmol) and methanol (100 mL), and thinoyl chloride (9.3 mL, 126.5 mmol) was added slowly at 0° C. The reaction mixture was then heated to reflux for 1.5 hours. The volatiles were removed under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The solvents were removed under reduced pressure to get the title compound as a solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:15]([O:13][CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCC(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of 20.3 g (0.115 mol) of 4-phenylcyclohexanol, 14.2 ml (O.1S mol) of acetanhydride and 29 ml of triethylamine are added, with stirring and at ambient temperature, 2.3 g (0.02 mol) of 4-dimethylaminopyridine, a clear solution being produced in an exothermic reaction. This is heated to 80° C. for 3 hours and the reaction mixture is then poured into ice water. The crystalline product precipitated is suction filtered, dissolved in ether, washed with sodium bicarbonate solution, dried and evaporated down in vacuo. 23 g (92% of theory) of O-acetyl-4-phenylcyclohexanol are obtained. The product is obtained initially as an oil but crystallises when left to stand. Melting point: 43-45° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:31])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1.I[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:31])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of diisopropylamine (951 μL, 6.79 mmol) in dry tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (1.56 g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was quenched with water (150 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining residue was further diluted with water (100 mL) and then extracted with ethyl acetate (1×250 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS m/e calcd for C17H24O6S2 (M+) 388.1014, found 388.1014.