Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)(C)C(OI(OC(=O)C(C)(C)C)C1C=CC=CC=1)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]=[CH:44][C:45]=1[Cl:46])[CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[C:35]([O:41][CH3:42])[CH:34]=1.ClCCCl>C(OC(C)C)(=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]=[CH:44][C:45]=1[Cl:46])[CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:38])=[C:35]([O:41][CH3:42])[CH:34]=1
Reactant: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)C(=O)OI(OC(=O)C(C)(C)C)c1ccccc1
Solvent: CC(=O)OC(C)C
Solvent: ClCCCl
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a solution of methanesulphonamide (79.6 mg, 0.837 mmol) and bis[(2,2-dimethylpropanoyl)oxy](phenyl)-lambda-3-iodane (630.0 mg, 1.553 mmol) in isopropyl acetate (6.0 mL) was added 4-[(3,4-dichlorobenzyl)oxy]-2-methoxybenzaldehyde (Preparation 25, 300.0 mg, 0.963 mmol) and 4 Å molecular sieves (500.0 mg). The reaction mixture was stirred for 5 minutes producing a thick suspension. 3,3′-(1,3-Phenylene)bis(2,2-dimethylpropanoic acid)-dirhodium(Rh—Rh) (2:1) (13 mg, 0.017 mmol) was added in one portion and the resulting mixture stirred at room temperature for 10 minutes. 1,2-dichloroethane (5 mL) was then added producing a green solution, which was stirred for further 18 hours under a nitrogen atmosphere at room temperature. The reaction mixture was then concentrated in vacuo and partitioned between DCM and aqueous solution of hydrochloric acid (2 M). The combined organics were dried through a phase separation Cartridge™ and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0 to 60% EtOAc in heptane to yield the title compound as pale yellow gum which solidified upon standing (140 mg, 41% yield):
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][C:14]=1[F:30])#[N:12].C(N(CC)CC)C>ClCCl.CCOC(C)=O.CCCCCC>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][C:14]=1[F:30])#[N:12]
Reactant: Cc1nccn1C(CCCO)c1ccc(C#N)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nccn1C(CCC=O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.114 mL, 1.305 mmol) in 3.0 mL of dichloromethane at −78° C. was added DMSO (0.185 mL, 2.60 mmol) dropwise. After 10 minutes, a solution of the alcohol from Step K (238 mg, 0.870 mmol) in 2 mL of dichloromethane was added dropwise, followed by triethylamine (0.424 mL, 3.04 mmol). The reaction was allowed to warm to room temperature over 30 minutes. The solution was poured into 80% EtOAc/hexane, washed with sat. aq. NaHCO3, water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled compound as a yellow oil which was used without further purification in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(C)(C)C)cc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 4-tert-butylphenylboronic acid (1.08 g, 6.05 mmol), potassium carbonate (1.67 g, 12.10 mmol) and palladium tetrakistriphenylphosphine (0.47 g, 0.40 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(4-(2-methyl-2-propanyl)phenyl)quinoline as a yellow oil. Mass Spectrum (ESI) m/e=346.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[CH3:6][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:13]=[C:12]([NH:21][C:22]([NH2:24])=[S:23])[N:11]=1)([CH3:9])[CH3:8].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:9][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[N:13]=[C:12]([NH:21][C:22]2[S:23][CH:2]=[C:3]([CH3:4])[N:24]=2)[N:11]=1)([CH3:6])[CH3:8]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)c1nc(NC(N)=S)nc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1csc(Nc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)n1
Yield: 45 %

Procedure:
Chloroacetone (0.17 g, 1.9 mmol) is added to a solution of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]thiourea in 25 mL of ethanol. The reaction mixture is warmed to reflux for 18 hours. The solution is poured into 100 mL of water and the pH is adjusted to 4 with saturated NaHCO3. The resulting precipitate is collected by filtration. Recrystallization from hexane gives 0.26 g (45%) of 4,6-bis(1,1-dimethylethyl)-2-[(4-methyl-2-thiazolyl)amino]-5-pyrimidinol; mp 171°-173° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(O[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)OCCCOCCOC1CCCCO1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccn(CCCOCCOC3CCCCO3)c12
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved in N,N-dimethylformamide (4 mL), cesium carbonate (1.30 g) was added, and the mixture was stirred at 40° C. for 4.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (380.2 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (8.00 g) in N,N-dimethylacetamide (112 ml) was added 2,6-di-t-butyl-4-methylphenol (0.24 g). Furthermore, to the resulting mixture were added 4-amino-3,5-dimethylphenol (6.47 g) and potassium t-butoxide (5.29 g) with stirring, and the resulting mixture was stirred at 60° C. for 30 minutes. After stirring, water (4 ml) was added to the reaction mixture, and furthermore water (120 ml) was added dropwise over a 2-hour interval, and then the resulting mixture was cooled gradually to room temperature. The crystalline solid precipitated was collected by filtration, washed with water (80 ml) and dried in vacuo to afford the title compound (11.45 g, yield: 93%) as a yellow crystalline solid.
Reaction SMILES: [C:1]([N:5]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:24]=[O:25].[Cl-].[NH4+]>O1CCCC1.CN(C)CCN(C)C>[C:1]([N:5]1[C:17]([CH2:24][OH:25])=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)n1cc2c(n1)c(=O)[nH]c1ccccc12
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)n1nc2c(=O)[nH]c3ccccc3c2c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A stirring solution of 2-tert-butyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (10.0 g, 41.4 mmol) in tetrahydrofuran (400 mL) and N,N,N′,N′ tetramethylethylenediamine (28 mL) was placed under an atmosphere of nitrogen and cooled to 0° C. n-Butyllithium (2.5M solution in hexanes, 49.7 mL, 124 mmol) was added dropwise over 30 minutes via an addition funnel. The resulting suspension was stirred at 0° C. for 15 minutes at which point paraformaldehyde (10.0 g, 333 mmol) was added in portions over 2 minutes. The suspension was allowed to warm to ambient temperature and stir for 2 hours. Additional paraformaldehyde (5.0 g, 167 mmol) was added and the resulting suspension stirred for 1.5 hours. Saturated aqueous ammonium chloride (150 mL) was added carefully and the mixture transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layers were concentrated to a brown solid which was triturated with acetonitrile (100 mL). The solid was isolated by filtration and the filter cake was washed with additional acetonitrile (100 mL). The cake was dried in a vacuum oven at 65° C. overnight to yield 5.0 g of 2-tert-butyl-1-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan solid. 500 mg of this material was crystallized from hot acetonitrile (100 mL) and isolated by filtration to yield 288 mg of 2-tert-butyl-1-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan solid, mp 295-297° C. Anal. calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.26; H, 6.64; N, 15.54.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3nsc4cc(F)ccc34)CC2)c(O)c1
Yield: 97 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1 mmol), NaHCO3, (0.94 g, 11.1 mmol), KI (100 mg) and CH3CN (100 ml) was stirred at reflux under N2 for 65 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H2O (1x) and brine (3x) and after drying with MgSO4 the solvent was evaporated to give 4.2 g of a dark solid. Three consecutive recrystallizations from EtOH provided 2.1 g (48%) of glittery beige crystals m.p.=135°-137° C. ANALYSIS: Calculated for C23H25FN2O3S: 64.47%C 5.88%H 6.54%N Found: 64.44%C 5.69%H 6.29%N
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.Cl.[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([CH3:14])[CH:24]=3)=[CH:33][CH:32]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(NC(=O)CC3NC(=O)NC3=O)cc2)c2ccccc2n1

Procedure:
Commercially available (+/−) hydantoin-5-acetic acid (100 mg, 0.63 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (213 mg, 0.63 mmol) were warmed in 1 mL dry DMSO and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 116 mg (46%) of a white waxy solid. MS found: (M+H)+=406.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][C:60]([F:64])([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (150 mg, 0.355 mmol), 1,1′-(azodicarbonyl)dipiperidine (179 mg, 0.709 mmol) in tetrahydrofuran (7.5 mL) was added tri(n-butyl)phosphine (0.177 mL, 0.709 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.259 mL, 3.55 mmol) was added to the reaction mixture. The mixture was stirred at 65° C. for 15 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102.9 mg, 0.204 mmol, 57%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH:6]1[CH2:18][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)[CH3:5].C(N(CC)CC)C.[O:36](C(OC(C)(C)C)=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40]([O:39][C:37]([N:10]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=2[C:8]2[CH2:7][CH:6]([C:4]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])([C:3]([O:2][CH3:1])=[O:28])[CH3:5])[CH2:18][C:9]1=2)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
130 mg (0.31 mmol) (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester were dissolved in 7 mL CH2Cl2 at RT. 90 μL (0.62 mmol, 2 eq) triethylamine, 4 mg (0.031 mmol, 0.1 eq) DMAP and 81 mg (0.37 mmol, 1.2 eq) BOC2O were added. The reaction mixture was stirred for 2 hours. The reaction was quenched with 10 mL of an aqueous 1M solution of HCl. The organic layer was separated and the aquous layer was washed with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield to 152 mg (94%) (RS,SR)-2-(1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder, M: 535 (MNH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 61 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-chloro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 185°-186° C. (from water). Yield: 61% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[F:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2ccc(Oc3ccccc3F)nc2n1
Temperature: 4 °C
Yield: 58.2 %

Procedure:
The procedure is similar to that described in Example 37, but starting with 2-amino-7-chloro-1,8-naphthyridine (18 g), 2-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (24 g; m.p. 202° C.) is dissolved in boiling ethanol (200 cc). After 16 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(2-fluorophenoxy)-1,8-naphthyridine (14.9 g) is produced, m.p. 206° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2Cl)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.89 g, 5.6 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.67 g, 5.6 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-(2-Chlorophenylsulfonyl)benzenamine (1.00 g, 3.7 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown solution was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The organics were combined, washed with water, dried (MgSO4), filtered and the solvent distilled to yield a tan solid. Recrystallization from methylene chloride/hexane yielded the title propanamide (1.43 g, 94%) as an off-white solid; mp 136°-138° C. 1H-NMR (250 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 7.57 (s, 1H, OH), 7.67 (m, 3H, aromatic), 7.88 (d, 2H, J=8.8 Hz, aromatic), 8.02 (d, 2H, J=8.8 Hz, aromatic), 8.26 (d, 1H, J=6.6 Hz, aromatic), 10.46 (s, 1H, NH). MS (CI, CH4): 408(M+1). Analysis for C16H13ClF3NO4S: Calculated: C, 47.13; H, 3.22; N, 3.43 Found: C, 46.93; H, 3.17; N, 3.40
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[I:10]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Cl)ncc1I
Temperature: 55 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (0.5 g, 3.48 mmol) in sulfuric acid (2.5 mL) was added N-iodosuccinimide (0.825 g, 3.48 mmol) portionwise at room temperature. The mixture was stirred at 55° C. for 2 hours. The reaction mixture was poured into ice water (10 mL) and 8 M NaOH (20 mL) was added slowly, after which the dark brown solution turned pale yellow. The aqueous layer was extracted with CH2Cl2 (2×20 mL). The organic layers were washed with brine (10 mL) and concentrated in vacuo onto silica gel. Dry flash chromatography, eluting with 25% EtOAc:c-Hex, gave 2-chloro-5-iodo-4-methoxypyridine as a white crystalline solid (0.169 g, 0.760 mmol, 22% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][C:28]2[N:31]([CH2:44][C@@H:45]3[CH2:47][O:46]3)[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[C:27]=2[CH2:26]1)(=[O:24])=[O:23]>CCO.ClC(Cl)C>[CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:47][C@H:45]([OH:46])[CH2:44][N:31]4[C:28]5[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][C:27]=5[C:33]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=5)=[N:32]4)[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Reactant: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Solvent: CCO
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc2c(n1)n(C1CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC1)c(=O)n2C
Temperature: 80 °C
Reaction time: 16 h
Yield: 112.3 %

Procedure:
To a stirring solution of 0.24 g (0.0009 mol) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g (0.0005 mol) of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was heated to 80° C. and stirred for 16 h and concentrated. The crude product was then dissolved in CH2Cl2 (40 mL) and purified using flash chromatography (0-6% MeOH/CH2Cl2) affording 0.38 g (97%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C31H39F3N8O4S, 676.28. m/z found, 677.28 [M+H]+. 1H NMR (400 MHz, CDCl3):7.71 and 7.67 (A and B of AA′BB′ quartet Jab=8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz, 1H), 4.58 and 4.56 (A and B of AB quartet, Jab=14.5 Hz, 2H), 4.36 (tt, J=12.1 Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m, 2H), 3.33 (s, 3H), 3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m, 2H), 2.88 (s, 3H), 2.77 (qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m, 3H), 2.21 (t, J=11.6 Hz, 1H), 1.75 (d, J=11.6 Hz, 2H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>C(O)C>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CC(O)CN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCC(C)O)ncc2c(=O)[nH]1
Yield: 83.4 %

Procedure:
In a similar manner to Example 13 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and 1-amino-2-propanol (0.97 g) in ethanol (15 ml) for 40 hours yielded the title compound 0.37 g, m.p. 212.5°-214° C. (recrystallised from methanol).