Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:14]=[C:8]2[CH:7]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:14]=[C:8]2[CH:7]=1
Reactant: COC(=O)/C=C/c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of (E)-3-{2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-acrylic acid methyl ester (450 mg, 0.86 mmol) and 10% palladium on carbon (0.2 g) in MeOH (20 mL) was stirred under a hydrogen atmosphere for 2 h, and the resulting mixture was filtered. The resulting solution was concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: gradient from 100% hexane to 80% hexane/20% EtOAc over 1.0 min., 80% hexane/20% EtOAc for 3 min., gradient to 50% hexane/50% EtOAc over 3.5 min., 50% hexane/50% EtOAc for 14.6 min,) to give 3-{2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-propionic acid methyl ester (208 mg, 46%):
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[CH:5]=[C:4]([C:1](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NNC(N)=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 62.8 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), semicarbazide hydrochloride (0.5 g), and pyridine (0.35 g) in ethanol (20 ml) was stirred and refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtered, and recrystallized from methanol to give a powder of 3'-(2,4-difluorophenoxy)-4'-methanesulfonamidoacetophenone semicarbazone (1.1 g).
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].CO>CS(C)=O.O>[CH3:12][C:2]([O:23][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(C(=O)C(C)(C)Br)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)C(C)(C)Oc2cc(C)cc(C)c2C)cc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
2-bromo-2-methyl-1-(4-methylphenyl)-1-propanone (422 g) in dimethyl sulfoxide (DMSO, 681 mL) was added dropwise to a solution of 2,3,5-trimethylphenol (136.19 g) and potassium carbonate (276.4 g) in DMSO (681 mL), followed by stirring at 35° C. for 24 hours. To the mixture were added dropwise methanol (953 mL) warmed to 55° C. and then water (953 mL). The mixture was stirred at 55° C. for 30 minutes and then at 40° C. for 1 hour. Precipitated crystals were filtered and suspended in methanol (2043 mL). Water (681 mL) was added to the suspension and the mixture was stirred at 40° C. for 1 hour. Precipitated crystals were filtered to obtain the title compound (257.98 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH3:10][Mg]Br.CO.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[CH3:10])=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)c1ccc(F)nc1
Yield: 94.6 %

Procedure:
A clear solution (prepared by filtration of a slightly cloudy suspension) of 6-fluoronicotinaldehyde (Frontier Scientific, Logan, Utah; 9.88 g, 79 mmol) in THF (100 mL) was added dropwise via addition funnel to a solution of methylmagnesium bromide (3.0 M in diethyl ether; 31.6 mL, 95 mmol) in THF (280 mL) at −6° C. (Addition was completed over about 20 min; reaction temperature kept below −5° C. during addition.) MeOH (10 mL) was then added (dropwise), followed by saturated aqueous NH4Cl (300 mL) and sufficient water to dissolve the precipitate. EtOAc (200 mL) was then added, and the organic layer was separated. The aqueous layer was extracted with DCM (2×150 mL), and all organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(6-fluoropyridin-3-yl)ethanol (10.55 g, 95% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.0 Hz, 1H) 7.85 (td, J=8.1, 2.5 Hz, 1H) 6.92 (dd, J=8.5, 2.8 Hz, 1H) 4.98 (q, J=6.5 Hz, 1H) 2.21 (br. s., 1H) 1.53 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH3:11])[C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[N:26]=[C:27]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:28]([CH3:34])=[N:29]2)=[O:23]>CN(C=O)C.C(Cl)Cl>[C:36]([NH:35][C:27]1[C:28]([CH3:34])=[N:29][C:30]2[C:25]([N:26]=1)=[C:24]([C:22](=[O:23])[CH2:21][CH:5]([C:4](=[O:10])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH3:11])[C:6]([O:8][CH3:9])=[O:7])[CH:33]=[CH:32][CH:31]=2)([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)(OC)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 4,4-dimethoxy-3-oxovalerate (Sigma Aldrich, 0.127 ml, 0.744 mmol), K2CO3 (EMD Biosciences, 0.135 ml, 2.231 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.25 g, 0.744 mmol) in DMF (2.97 mL) was stirred at RT for 2 d. Reaction mixture was diluted with DCM and washed with alternating water and brine washes (2×) to remove DMF. The organic layer was concentrated and advanced to the next step. m/z (ESI, +ve) 446.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]N(CCN(C)C)C.C([Li])(CC)C.COS(OC)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH:13]1[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2)CC1
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CC1CC(N2CCCCC2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-tert-Butoxycarbonyl-[1,4′]-Bipiperidine 1 (5.1 g, 19.0 mmol), TMEDA (19 ml) in dry Et2O (40 ml) at −78° C. is slowly added a solution of sec-butyllithium (19.0 ml, 24.7 mmol, 1.3 M in cyclohexanes) over a period of 30 min. The mixture is stirred at −78° C. for 3 hr, and then is treated with a solution of Dimethylsulfate (3.6 g, 28.5 mmol) in Et2O (5 ml). The cooling bath is removed and the reaction mixture is stirred at ambient temperature for 16 hr. After cooling to 0° C., the reaction mixture is quenched with water, extracted with Et2O (5×100 ml), and the combined ether layers is dried over K2CO3. The solvent is removed in vacuo and the residue is purified on silica gel chromatography (eluting 40% ethyl acetate in hexane) to give 2.51 g of 1′-tert-Butoxycarbonyl-2′-methyl-[1,4′]-Bipiperidine, 2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>CO>[NH2:21][C:20]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CCOC=C(C#N)C#N
Solvent: CO
Product: N#Cc1cnn(-c2ccccc2C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(2-(Trifluoromethyl)phenyl)hydrazine (CAS no. 365-34-4) (10.0 g, 56.77 mmol) was dissolved in MeOH (150 mL) under nitrogen at 0° C. 2-(ethoxymethylene)malononitrile (6.93 g, 56.77 mmol) added portionwise over 2 mins and the mixture stirred at ˜0° C. for 0.5 hours. The reaction was heated at reflux for 2 hours. Further methanol (15 mL) was added to aid mobility. The mixture was allowed to cool and was evaporated to give the product (14.3 g, 100%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 6.63 (2H, s), 7.53 (1H, d), 7.73 (1H, s), 7.74-7.77 (1H, m), 7.82-7.86 (1H, m), 7.91-7.94 (1H, m); m/z (ESI+) (M+H)+=253; HPLC tR=1.60 min.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([NH2:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[O:16][CH2:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[N:12]=4)[C:25](=[O:26])[CH:24]=3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3c(c2)OCO3)[nH]c2nc(Cc3ccccc3)nn12
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of 3-benzyl-1H-1,2,4-triazol-5-amine (100 mg, 0.57 mmol) in n-BuOH (3 ml) was added ethyl 3-(2H-1,3-benzodioxol-5-yl)-3-oxopropanoate (200 mg, 0.85 mmol) and 4-methylbenzene-1-sulfonic acid (4 mg, 0.02 mmol). After stirring overnight at reflux, the solids were collected by filtration and washed with ethyl acetate (3×10 mL), methanol (3×10 ml) and dried to give 5-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid (50.2 mg, 25%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][OH:24])[C:21]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1c(N)cccc1CO
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cccc(CO)c1C
Yield: 65.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (1.32 g, 5 mmol) and 3-amino-2-methylbenzyl alcohol (0.82 g, 6 mmol) in dioxan (25 ml) was heated at reflux for 1.5 hours, then the solvent evaporated. Aqueous sodium bicarbonate was added, the product extracted into dichloromethane, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(3-hydroxymethyl-2-methylphenylamino)-8-methoxyquinoline (1.20 g, 66%), m.p. 186°-188°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]2[CH:26]=[CH:27][S:28][C:24]=2[CH:23]=1>ClCCCl>[Br:1][C:27]1[S:28][C:24]2[CH:23]=[C:22]([O:21][CH3:20])[CH:30]=[CH:29][C:25]=2[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2ccsc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: COc1ccc2cc(Br)sc2c1
Temperature: 70 °C
Yield: 82.2 %

Procedure:
N-bromosuccinimide (14.70 g, 82.59 mmol) and p-toluenesulfonic acid (2.70 g, 15.68 mmol) were added to a solution of benzothiophene (3) (15.10 g, 92.07 mmol) in 1,2-dichloroethane (300 ml). The mixture was maintained at 70° C. for 35 min, cooled in an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under vacuum to give 22.00 g as an oil. Crystallisation from pentane afforded a white solid (16.50 g, 74%), mp 62° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[C:23](C(F)(F)F)[C:22](C)=[C:21]3[C:17]=2[C:18]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:19]=2[NH:20]3)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6]>OS(O)(=O)=O>[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[C:2]([C:1]([OH:4])=[O:3])[C:22]([CH3:23])=[C:21]3[C:17]=2[C:18]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:19]=2[NH:20]3)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6]
Reactant: CC(=O)O
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c3[nH]c4ncc(C)cc4c23)c1
Agent: O=S(=O)(O)O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 120 °C

Procedure:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-7-(trifluoromethyl)-9H-pyrido[2,3-b]indole acetate (3.6 g, 7.3 mmol) was dissolved in concentrated H2SO4 (30 mL) and heated at 120° C. for 30 min. The reaction was cooled to room temperature and poured over ice affording a white precipitate. The resulting suspension was filtered, rinsed with H2O (3×30 mL) followed by IPA (3×10 mL) and dried in vacuo to 3.2 g (quant.) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 8.02-8.07 (m, 2H), 7.89 (t, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 3.43 (q, 2H), 2.85 (s, 3H), 2.28 (s, 3H), 1.18 (t, 3H). MS (ES) [m+H] calc'd for C22H20N2O4S, 409; found 409.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH3:17]>C1COCC1>[NH2:7][C:8]1[C:9]([CH3:17])=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1cc(C#N)cc(C)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(C)c1N
Temperature: 25 °C

Procedure:
Step AN2. To the suspension of 0.26 g of lithium aluminum hydride in 30 mL of THF was added dropwise a solution of 0.49 g of 4-amino-3,5-dimethylbenzonitrile in 5 mL of THF. The reaction mixture was stirred at reflux for 3 hours and cooled to room temperature. The reaction mixture was quenched with 1.0 mL of 1.0 N NaOH aqueous solution. The precipitate was filtered off and the solvent was evaporated in vacuo to provide the crude product, which can be used without purification. A portion of the crude product was purified by preparative HPLC. LCMS (method B) RT 0.152 min., (2M+H)+ 301. 1H NMR (500 MHz, CD3OD) δ 7.04 (s, 2 H), 3.95 (s, 2 H), 2.25 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)=[C:10]([CH3:22])[CH:9]=2)=[CH:4][C:3]=1[C:23]1[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=1.[BH4-].[Na+].CO>C1COCC1.O>[CH:28]([N:26]1[CH:27]=[C:23]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[C:10]([CH3:22])[CH:9]=3)[CH:4]=2)[N:24]=[N:25]1)([CH3:30])[CH3:29]
Reactant: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
BF3Et2O in THF (47-49%) (0.87 mL, 2.46 mmol) was added to a solution of [4-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-methyl-phenyl]-morpholino-methanone (200 mg, 0.46 mmol) in THF (10.0 mL) at 0° C. The reaction mixture was stirred for 30 min, NaBH4 (93.5 mg, 2.46 mmol) was added at 0° C., reaction mixture was slowly warmed to RT, stirred for 16 h. Reaction mixture was again cooled to 0° C., added MeOH (5.0 mL) and heated to 70° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 2% MeOH in DCM. Product was further purified by Prep.HPLC furnished 30 mg (Yield: 15.5%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:13](=[O:20])(=[O:19])[NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]2[OH:12].N1C=CC=CC=1.[O:27]1[CH2:32][CH2:31][N:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:29][CH2:28]1.Cl>O>[C:15]([NH:14][S:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:33]([N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)(=[O:35])=[O:34])[C:7]=1[OH:12])(=[O:20])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(N)cccc2c1O
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NS(=O)(=O)N3CCOCC3)cccc2c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a mixture of 9 g. of 5-amino-2-tert-butylsulfamoyl-1-naphthol with 90 ml. of pyridine were added portionwise under ice-cooling and stirring 11 g. of morpholinosulfonyl chloride and stirring was continued at room temperature for 20 hours. Thereafter, 10 ml. of water were added and stirring was carried out for further 1 hour. Into a mixture of 115 ml. of conc. hydrochloric acid with 400 ml. of ice-water was poured the above reaction mixture to separate a solid precipitate, which was then collected on a filter funnel and washed with water. The product was dissolved in an alkaline solution of 6 g. of sodium hydroxide in 150 ml. of water, insolubles were filtered off, the filtrate was poured into a mixture of 15 ml. of conc. hydrochloric acid with 150 ml. of ice-water to separate a solid precipitate. The precipitate was collected on a filter funnel, washed well with water and then dried to afford 9.6 g. of the desired product in a yield of 72%. mp. 105°-110° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:30][C:25]([CH3:31])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: COC(=O)C(C)(C)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (4 g), methyl 6-bromo-2,2-dimethylhexanoate (5.8 g) (prepared according to the method described in Patent EP 108 592), silver carbonate (2.3 g) and toluene (150 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 95-5, brown oil)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][O:47][Si](C(C)(C)C)(C)C)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][OH:47])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 259E, 207 mg, 0.275 mmol) in THF (2.0 mL) at room temperature was added TBAF (0.413 mL, 0.413 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-70% EtOAc/hexanes) to give ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol, 64%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[CH:27][C:26]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([C:23]2[C:24]3[N:25]=[C:26]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)[CH:27]=[N:28][C:29]=3[C:20]([C:10]3[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[Cl:19])=[CH:21][CH:22]=2)=[O:40])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: CCN1CCN(Cc2cnc3c(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc(C(=O)O)c3n2)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2cnc3c(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc(C(=O)Nc4cccnc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 82.1) and stirring the reaction mixture for 12 h at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.24 min (System 1); TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[Cl:25][C:26]1[CH:31]=[C:30]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[OH:1])[S:10][C:11]=3[CH:17]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 60 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To the mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (265 mg, 1 mmol) and cesium carbonate (651 mg, 2 mmol) in 3 ml of NMP was added 2-chloro-4-fluoropyridine (263 mg, 2 mmol). The reaction mixture was stirred at 60° C. for 20 hours. The crude reaction mixture was filtered and then purified on prep HPLC to give (1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol as powder (341 mg, 0.9 mmol). ES/MS m/z 376.0 (MH+).