Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3]O.[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.CC[O:34]CC>>[C:6]([O:34][O:5][CH2:1][CH2:2][CH3:3])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOCC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCO
Solvent: c1ccncc1
Product: CCCOOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
1,3-Propanediol (1.053 g, 13.84 mmol), trityl chloride (3.50 g, 12.6 mmol) and anhydrous pyridine (5 ml) were combined in a flame-dried round-bottomed flask. The reaction mixture was stirred overnight at room temperature. Ether was added to the reaction mixture and the solution was extracted with H2O, 1N HCl, H2O, and brine. The ether layer was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography (100 g silica gel; hexanes:ethyl acetate, gradient 8:1 to 6:1) to provide the pure ether compound 20, 1-O-trityloxy-propanol (1.85 g, 46.4% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20].Cl>ClCCl.C(N(CC)CC)C>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: OCc1ccccc1SCCCCCl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1SCCCCCl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, thermowell and addition funnel, under a nitrogen atmosphere, was added 78.4 ml of oxalyl chloride and 925 ml of dichloromethane. The reaction was cooled to -78° C. with a dry ice/acetone bath. Then 125.3 ml of distilled dimethylsulfoxide was added dropwise, maintaining the reaction temperature below -65° C. After the addition was complete, 138.4 g of 2-[(4-chlorobutyl)thio]benzyl alcohol was added in 300 ml of dichloromethane. After addition was complete, the mixture was stirred for 30 min., then 417.3 ml of triethylamine was added. The bath was allowed to warm gradually to room temperature and stirred overnight at this temperature. The reaction mixture was poured into a 12 liter flask containing a stirring mixture of 3100 g of crushed ice and 4730 ml of 1N HCl. After stirring for 30 min., the mixture was extracted with dichloromethane (3×300 ml) the organic solution was dried over magnesium sulfate, filtered and concentrated to a brown oil. The product was further purified by column chromatography on silica gel, eluting with 10% ethyl acetate in hexane to give 117.7 g of the pure product as an oil. 1H-NMR (CDCl3) δ 1.8-2.0(m,4H); 3.0(t,2H); 3.6(t,2H); 7.2-7.6(m,3H); 7.8(m,1H); 10.4(s,1H).
Reaction SMILES: [CH:1]([C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:5]#[N:6])([CH3:3])[CH3:2].C=O.[CH:34](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:34])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: COc1ccc(C(C#N)(CCCNCCOc2ccccc2OC)C(C)C)cc1OC
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C(C#N)(CCCN(C)CCOc2ccccc2OC)C(C)C)cc1OC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 2.35 g of alpha-isopropyl-alpha-[3-[N-[2-(2-methoxyphenoxy)ethyl]amino]propyl]-3,4-dimethoxyphenylacetonitrile, 8 ml of 37% formalin, and 16 ml of 90% formic acid was stirred for 1 hour at 110° C. After cooling, to the mixture were added water and potassium carbonate to make it alkaline. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.30 g of the desired compound as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C(O)C>C1(=O)OC(C)CO1>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[CH3:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1COC(=O)O1
Solvent: CCO
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 24 h

Procedure:
To a suspension of potassium carbonate (0.71 g, 10 mmol, 1.3 equiv) and 2-amino-3-methyl-5-chloro-N-(diethyl-λ4-sulfanylidene)benzamide (1.42 g, 3.96 mmol) in propylene carbonate (20 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (1.35 g, 4.35 mmol, 1.10 equiv.) in propylene carbonate (10 mL) at room temperature. After 24 h at this temperature, the mixture was poured onto water and spiked with ethanol under vigorous stirring. The resulting solids were collected by filtration and contained pure title compound (1.57 g, 73%).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:8])([CH3:5])([CH3:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[C:2]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:30]([C:29]1[C:25]([C:19]2[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[N:26][O:27][C:28]=1[CH3:33])=[O:31])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Yield: 100.6 %

Procedure:
N-t-butyloxycarbonyl-1,6-diaminohexane hydrochloride salt (1.02 g, 4.03 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.11 g, 4.03 mmol) were converted to 1.84 g of the title compound by the procedure of Preparation 1. (100%). EA calculated for: C22H29N3O4ClF: C, 58.21; H, 6.44; N, 9.26. Found: C, 57.97; H, 6.20; N, 9.43. MS(IS) m/z 454 (M+)
Reaction SMILES: C(N(CC)CC)C.Cl.CN(CCCN=C=NCC)C.[O:20]=[C:21]1[NH:25][CH:24]([C:26]([OH:28])=O)[CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:22]1.[N+]([O-])(O)=O.[N+:39]([O:42][CH2:43][CH2:44][NH2:45])([O-:41])=[O:40]>CN(C)C=O>[N+:39]([O:42][CH2:43][CH2:44][NH:45][C:26]([CH:24]1[CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:22][C:21](=[O:20])[NH:25]1)=[O:28])([O-:41])=[O:40]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2ccccc2)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
0.07 ml of triethylamine and 90 mg of 1-(N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, whilst ice-cooling and stirring, to a solution of 105 mg of 2-oxo-5-phenylthiazolidine-4-carboxylic acid and 79.5 mg of N-(2-nitrooxyethyl)amine nitrate in 10 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature overnight. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residual yellow oil was triturated with diethyl ether. The crystals which precipitated were collected by filtration and purified by column chromatography through silica gel, using a 40:1 by volume mixture of methylene chloride and methanol as the eluent, to give 34 mg of the title compound as pale yellow crystals, melting at 139°-140° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH:5]([C:16]([OH:18])=[O:17])[S:6][CH2:7][C:8](O)([CH3:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O=S(Cl)Cl.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:9]([C:8]1([CH3:14])[O:17][C:16](=[O:18])[CH:5]([CH2:4][C:3]([OH:2])=[O:19])[S:6][CH2:7]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1

Procedure:
2.7 g of 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester and 1.25 g of SOCl2 are stirred for 2 hours in 40 ml of chloroform at room temperature. The mixture is boiled briefly. After cooling, 0.5 ml of piperidine, dissolved in 20 ml of chloroform is added thereto. The resultant mixture is further stirred for 1 hour at 30°. After the usual working up, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:14]
Reactant: CN=C=O
Reactant: CC1=NC(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)ON=C1SC(C)(C)N=C1C
Reaction time: 16 h

Procedure:
20.0 g (0.126 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are dissolved in 100 ml of chloroform. To the solution are added 15 ml (0.252 mol) of freshly distilled methyl isocyanate as well as 3 drops of triethylamine. The mixture, which warms slightly after a short time, is left to stand at room temperature for 16 hours. Subsequently, the slightly turbid solution is filtered, and the solvent and excess methyl isocyanate are distilled off in vacuo. The oily residue is purified chromatographically on 250 g of silica gel using ethyl acetate/n-hexane (1:1) for the elution. The solvent is removed by evaporation, and the resulting residue is recrystallized from methylene chloride/n-hexane/diethyl ether to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(methylcarbamoyl) oxime as white crystals, m.p. 90°-92° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1S(O)(=O)=O.[CH2:10](O)[CH:11]([CH3:13])[CH3:12].[C:15](O)(=O)/[CH:16]=[CH:17]/C(O)=O>C(O)C>[N:1]1[C:12]2[CH2:15][CH2:16][CH2:17][CH2:13][C:11]=2[CH:10]=[C:4]([NH:3][C:2]2[NH:1][CH2:5][CH2:4][N:3]=2)[CH:5]=1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC(C)CO
Solvent: CCO
Product: c1nc2c(cc1NC1=NCCN1)CCCC2
Yield: 59 %

Procedure:
A mixture of the above solid (0.221 g, 1.49 mmole), 2-imidazoline-2-sulfonic acid (0.805 g, 5.4 mmole) and isobutyl alcohol (4 mL) was refluxed for 18 hours. The solvent was removed in vacuo and the residue was flash chromatographed over silica gel (eluent: 10:2:1 v/v/v ethyl acetate-methanol-triethylamine). The product was obtained in 100% yield (0.337 g) as a pale yellow solid. The above solid was treated in ethanol with 1.0 equivalent of fumaric acid to give a fumarate as a white solid (59% yield): mp 201-203° C. Anal. Calcd. for C12H15N4·1.5C4H4·0.5H2O: C, 54.13; H, 5.76; N, 14.04. Found: C, 54.04; H, 5.96; N, 13.69.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Br)cc(Br)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(Br)nc(OCc2ccccc2)n1

Procedure:
4,6-dibromo-2-(methysulfonyl)pyrimidine (Compound III-3) (1.5 g, 0.00476 mol) was dissolved in toluene, and benzyl alcohol (Compound II-64) (0.515 g, 0.00476×1.0 mol) was added thereto. While cooling with ice, 60% sodium hydride (0.21 g, 0.00476×1.1 mol) was added while stirring. After stirred for 6 hours, the reaction solution was poured into water and extracted with toluene. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, 100 ml, ethyl acetate/hexane=20 ml/400 ml) to obtain the compound (I-81) as an oily product from the fraction of 100 ml to 120 ml.
Reaction SMILES: NC1C(C)=CC([N:8]([CH2:16][CH2:17][C@@H:18]2[CH2:20][C@@H:19]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH2:23][CH2:22]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=NC=1.[CH3:35][C:36]1([C:39]([OH:41])=O)[CH2:38][CH2:37]1.CN(C(O[N:50]1N=N[C:52]2[CH:53]=[CH:54][CH:55]=[N:56][C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[N:32][C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C@H:19]3[CH2:20][C@H:18]3[CH2:17][CH2:16][N:8]([C:54]3[CH:55]=[N:56][C:51]([NH:50][C:39]([C:36]4([CH3:35])[CH2:38][CH2:37]4)=[O:41])=[CH:52][CH:53]=3)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:26][CH2:25]2)=[N:28][CH:29]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1cc(N(CC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)C(=O)OC(C)(C)C)ncc1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(NC(=O)C2(C)CC2)nc1

Procedure:
tert-butyl (5-amino-4-methylpyridin-2-yl)(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)carbamate (80 mg, 0.17 mmol) from Step 2 of Example 30a, 1-methylcyclopropane-1-carboxylic acid (19.2 mg, 0.19 mmol), HATU (84 mg, 0.22 mmol) and triethylamine (68.5 mg, 0.68 mmol) were added in DMF (1.7 mL) at room temperature for 2 days. The reaction was added ethyl acetate (20 mL, washed with sodium bicarbonate saturated solution (10 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCOCC1.Cl.C(Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 ml) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 ml) and to it were slowly added benzyl bromide (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (3:1 n-Hexane/EtOAc) to give a colorless oil (4 mg, 80% yield): 1H NMR (300 MHz, CDCl3) 0.91˜1.74 (m, 18H); 1.89 (m, J=12.6 Hz, 1H); 2.07˜2.21 (m, 1H), 2.29˜2.48 (m, 2H); 2.63˜2.69 (m, 1H); 2.87 (s, 1H); 3.09 (d, J=18.3 Hz, 1H); 3.68 (dd, J=13.4 Hz, 2H); 6.82˜6.93 (m, 2H); 7.15 (d, J=8.3 Hz, 1H); 7.25˜7.38 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O>C(O)C.Cl.C(O)(C)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:21][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=2)=[O:10])[CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(Cl)c(O)c(OC)c2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A solution of 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (200 mg, 0.869 mmol) and 3-chloro-4-hydroxy-5-methoxybenzaldehyde (194 mg, 1.04 mmol) in ethanol (2 mL) and 5 N HCl in isopropanol (1 mL) is stirred at rt for 18 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (5 mL) and THF (5 mL) and treated with Pd/C (150 mg, 10% Pd). The slurry is hydrogenated under 1.8 bar of H2 for 18 h. The mixture is filtered over celite, the solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (208 mg) as a colourless oil; LC-MS: tR=1.10 min, [M+1]+=401.12; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.46-7.30 (m, 5H), 6.83 (d, J=1.8 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 3.88 (s, 3H), 3.16 (t, J=7.6 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.91 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:34]([CH3:38])[CH2:35][CH2:36][OH:37])[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:37][CH2:36][CH2:35][CH:34]([C:22]1[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=1)[CH3:38])(=[O:3])=[O:2]
Reactant: CC(CCO)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (11.1 g., 58.1 mM) is added to a solution of 3-(3,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexane. Yield: 24.63 g. (84%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.[F:36][C:37]1[CH:38]=[C:39]([CH:55]=[CH:56][CH:57]=1)[CH2:40][N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:44]4[CH:43]=[N:42][N:41]([CH2:40][C:39]5[CH:55]=[CH:56][CH:57]=[C:37]([F:36])[CH:38]=5)[CH:45]=4)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (3-fluoro-5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)carbamate (intermediate 66T) (150 mg, 0.24 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (82 mg, 0.27 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.012 mol) and sodium carbonate (76 mg, 0.72 mmol) in toluene/ethanol/water (10/10/2 mL) to afford 122 mg (crude) of the titled compound. MS: m/z=657.2 (M+1).
Reaction SMILES: ClCC([NH:5][C:6]([CH3:19])([CH3:18])[CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=O.NC(N)=S.[C:24](O)(=O)[CH3:25]>C(O)C>[CH2:24]([O:17][C:15](=[O:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][C:6]([NH2:5])([CH3:18])[CH3:19])[CH:9]=1)[CH3:25]
Reactant: CC(=O)O
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC(=O)CCl
Agent: NC(N)=S
Solvent: CCO
Product: CCOC(=O)Cc1cccc(CC(C)(C)N)c1
Yield: 63 %

Procedure:
A solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (Preparation 48) (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was reduced in vacuo, the residue dissolved in ethanol (150 ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The solvent was reduced in vacuo and the residue partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml). The organic extract was washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and reduced in vacuo. The residue was purified by strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluent was concentrated in vacuo giving the title compound as a yellow oil (2.68 g, 63%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.C(NC(C)C)(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1.Cl>ClCCl>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:28]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)Cc1cccc(CN)c1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (from Preparation 18, 0.56 g) and diisopropylamine (2.2 mL) in 10 mL dichloromethane was added pyridine-3-sulfonyl chloride (from Preparation 2, 0.601 g, 2.83 mmol) and the reaction was stirred at room temperature for 16 h. Aqueous 1N HCl was added and the solution was washed with CH2Cl2. The organic solution was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound. Purification via flash chromatography on silica gel (2:1 hexanes:EtOAc) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.71 (d, 1H), 8.04 (d, 1H), 7.37 (m, 1H),7.05 -7.24 (m, 4H), 5.87 (bs, 1H), 4.14 (s, 2H), 3.62 (s, 3H), 3.52 (s, 2H).