Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16](Cl)(=[O:18])=[O:17]>>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6])(=[O:18])=[O:17]
Reactant: CCNCCO
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: CCN(CCO)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-ethylamino ethanol and 2,4,5trichlorophenylsulfonylchloride using the method described in Description 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][CH2:12][CH2:13][N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.B(F)(F)F.[CH3:19]COCC.C[Li].[Cl-].[NH4+].[OH-].[Na+]>C1COCC1.C(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH3:19])[CH2:11][CH2:12][CH2:13][NH:14]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOCC
Reactant: c1cc2c(cc1C1=NCCC1)OCO2
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC1(c2ccc3c(c2)OCO3)CCCN1
Temperature: -78 °C
Yield: 19.8 %

Procedure:
To a −78° C. solution of 5-benzo[1,3]dioxol-5-yl-3,4-dihydro-2H-pyrrole (1.67 g, 8.83 mmol) in THF (60 mL) add boron trifluoride diethyl etherate (1.22 mL, 9.71 mmol) dropwise over 5 min. Stir the resulting cloudy reaction mixture at this temperature for 40 min, and then add methyllithium (1.6 M in diethyl ether, 27.5 mL, 44.1 mmol) dropwise via a syringe pump (about 1.1 mL/minute) over 20 min. Maintain the reaction temperature at −78° C. for 2.5 h and then warm to 0° C. over 1.5 h. Quench the reaction by the addition of water (50 mL) and saturated aqueous ammonium chloride (50 mL), then adjust the mixture to a pH of about 11-12 using aqueous 2 M NaOH, and extract with 9:1 methylene chloride/chloroform (3×330 mL). Dry the combined organic layer (MgSO4), filter and concentrate under reduced pressure to obtain a crude brown oil (˜2.6 g). Subject the crude residue (dry loaded on silica gel using CH2Cl2) to flash chromatography (120 g silica gel, gradient from 80:20 to 50:50 CH2Cl2/[90:10:1 CH2Cl2/MeOH/NH4OH]) to afford pure title compound (910 mg, 50%, >95% purity by 1H NMR) and impure title compound (358 mg, 20%, ˜85% purity by 1H NMR) as light brown oils. MS (ESI+): 206 (M+1)+; 1H NMR (300 MHz, CDCl3): δ 7.01 (d, J=1.8 Hz, 1H), 6.93 (dd, J=8.1, 1.8 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 5.92 (s, 2H), 3.12-3.05 (m, 1H), 3.00-2.92 (m, 1H), 2.06-2.00 (m, 1H), 1.88-1.69 (m, 4H), 1.40 (s, 3H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15]>>[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCCl
Product: ClCCOCCOCc1ccccc1

Procedure:
is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](C(F)(F)F)=[C:6]([CH:9]=1)C#N.C([O-])([O-])=O.[K+].[K+].C[N:21]([CH:23]=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:21])=[CH:6][CH:9]=1
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
5-FLUORO-2-(TRIFLUOROMETHYL)BENZONITRILE (compound 8h; Oakwood), K2CO3 (4 eq.) and DMF (5 mL) was shaken at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (20 mL), extracted with CHCl3 (3×20 mL), and concentrated. The residue was dissolved in THF/MeOH (10 mL/4 mL), and treated with HCl (1N, 3 mL) at room temperature for 12 h. The solvent was evaporated and the residue was diluted with CHCl3 (20 mL), neutralized with NH4OH (28% aqueous) and purified by column chromatography (CH3Cl/MeOH 10/1) to give:
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].[OH-].[Li+]>C(#N)C.O>[CH2:1]([N:3]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 93.9 %

Procedure:
Methyl 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-ethyl}thio)benzoate (0.085 g, 0.160 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml), then lithium hydroxide (0.008 g, 0.320 mmol) was added. The reaction was performed in an single node microwave oven (5 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water phase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.07773 g of 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethyl}thio)benzoic acid (yield 93.0%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH3:22])[C:18]=3[NH:23][C:24]([O:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH3:28])=[O:25])=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:27]([O:26][C:24]([NH:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)=[O:25])[CH3:28]
Reactant: COC(=O)c1ccccc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccccc3C(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-2-carboxylic acid methyl ester (0.21 mmol) in methanol was added 1N aqueous LiOH (2 mL) and stirred overnight at room temperature. The solution was stirred at 40° C. for 3 days. The mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:23]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.74) (0.485 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.08 g) which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)=[O:16])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 1-tert-butyl ester 5-methyl ester (1.5 g, 3.8 mmol) was dissolved in dichloroethane (26 mL) and the mixture was added to TFA (13 mL). The mixture was stirred at room temperature for 4 hrs. TLC indicated the reaction was complete. Solvent was evaporated by rotovap. The solid obtained was washed with EtOAc and water. After drying, 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester was obtained in 87% yield (1.128 g). MS (ESI) m/z 342.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(-c2ccc(F)cc2)c1
Yield: 59.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), 4-fluorophenyl boronic acid (457 mg, 3.27 mmol) and palladium (II) acetate gave the title compound as a white solid (373 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.52 (dd, J=5.4, 8.4 Hz, 2H), 7.42-7.38 (m, 3H), 7.12 (m, 2H), 5.18 (s, 1H), 4.62 (s, 1H), 2.66 (m, 6H), 1.72 (s, 6H), 2.01-0.83 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 125.0, 124.0, 123.8, 116.0, 116.0, 71.3, 55.9, 55.5, 47.6, 46.7, 29.6, 25.6, 24.8, 19.8 ppm. Purity: 98.0% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C23H27FN2O2.0.37 (CHCl3): C, 65.86; H, 6.47; N, 6.57. Found: C, 65.85; H, 6.69; N, 6.49.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][CH:23]([C:25](O)=[O:26])[CH3:24])[CH:18]=[CH:19][C:20]=1[Cl:21].N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH:5][C:25](=[O:26])[CH:23]([CH3:24])[NH:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: C[C@H](N)C(=O)O
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using β-cyclohexylalanine methyl ester (prepared from β-cyclohexylalanine (Bachem) using General Procedure K) and N-(3,4-dichlorophenyl)-D,L-alanine, the title compound, as a mixture of diastereomers about alanine, was prepared as an oil. The reaction was monitored by tlc (Rf=0.27 (second isomer) and 0.30 (first isomer) in 35% EtOAc/hexanes) and purification was by flash chromatography (35% EtOAc/hexanes).
Reaction SMILES: FC1C2SC=CC=2C([C:11](=[O:14])CC)=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1>CN(C)C=O>[Br:15][C:16]1[C:17]([CH:11]=[O:14])=[C:18]([F:23])[C:19]([F:22])=[CH:20][CH:21]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: CCC(=O)c1ccc(F)c2sccc12
Solvent: CN(C)C=O
Product: O=Cc1c(Br)ccc(F)c1F

Procedure:
In a similar manner to Example 9 Method A, 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one was prepared starting from 4-bromo-1,2-difluorobenzene (39.7 g). This was lithiated and reacted with dimethylformamide to give 6-bromo-2,3-difluorobenzaldehyde (41.3 g) as a yellow solid. The aldehyde was reacted with methyl thioglycolate (14.6 ml) to give methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (31.2 g) as a yellow solid. The ester was hydrolysed to give 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (37.25 g) as a yellow solid which was decarboxylated using copper and quinoline at 170-180° C. for 4 hours to give 4-bromo-7-fluorobenzo[b]thiophene (18.2 g) as a white solid, m.p. 47-48° C. This compound (7.4 g) was reacted with magnesium (0.85 g) and then with N-methoxy-N-methylpropionamide (5.6 g) to give 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one (2.1 g) as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Product: CC(=O)c1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-acetylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:24][C@H:23]([NH:25][C:26](=[O:41])[CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][NH:21]1)=[O:19])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:24][C@H:23]([NH:25][C:26](=[O:41])[CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][N:21]1[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1C(c1ccccc1)c1ccccc1
Yield: 57.2 %

Procedure:
To a solution of bromodiphenylmethane (0.4 g, 1.64 mmol) in butanone (10 ml) was added (2S,4S)-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid ethyl ester (36) (0.6 g, 1.64 mmol), K2CO3 (0.23 g, 1.64 mmol) and KI (0.27 g, 1.64 mmol). The mixture was heated under reflux for 18 hours, and then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gives 0.5 g the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:46][CH2:45][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:46][CH2:45][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:22])([F:23])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(O[C@H](c2cc(-c3ccccc3)ccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]2[CH:23]3[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:25][CH:17]2[CH2:18]4)[CH2:22]3)=[O:14])[CH2:9][CH2:8]1.O[Li].O.O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C1COCC1.CO.C(Cl)Cl>[CH:17]12[CH2:25][CH:21]3[CH2:20][CH:19]([CH2:24][CH:23]([CH2:22]3)[CH:16]1[O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]([CH2:6][O:5][CH2:4][C:3]([OH:32])=[O:2])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:12][CH2:11]1)=[O:14])[CH2:18]2
Reactant: COC(=O)COCC1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCC1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
To a stirred solution of 2-adamantyl 4-((2-methoxy-2-oxoethoxy)methyl)-4-phenylpiperidine-1-carboxylate (17.5 mg, 0.04 mmol) in THF (0.5 mL) and MeOH (1 mL) were added LiOH.H2O (8.3 mg, 0.2 mmol) and water (0.5 mL). The mixture was stirred at rt for 18 h and submitted directly to prep HPLC. The product from prep HPLC (8.3 mg) was stirred gently with MP-carbonate resin (75 mg), MeOH (2 mL) and CH2Cl2 (2 mL) for 22 h. The mixture was filtered and the resin beads collected were resuspended in 20:1 CH2Cl2/TFA (5 mL) overnight. The mixture was filtered and the filtrate was concentrated to leave crude material (2.5 mg). This material was purified by prep HPLC to afford the title compound (0.75 mg). LC-MS Method 1 tR=2.12 min, m/z=428.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C.O>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Yield: 15.2 %

Procedure:
To a stirred solution of 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.25 mmol) in ethanol (10 ml) was added 1N NaOH (1.26 ml, 1.26 mmol) solution at RT. The reaction mixture was refluxed for 24 h. The volatiles were removed under vacuum to afford a crude residue which was diluted with water. The aqueous layer was washed with ethyl acetate to remove non-polar impurities and then the pH was adjusted to 4-3 with 10% citric acid under cooling. Then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude residue which was purified via Prep-HPLC followed by Prep-TLC to obtain pure 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid as pale yellow solid (14 mg, 15%). LC-MS: 369 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:5]3[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: COC1CN(Cc2ccc(N)nc2)C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC1CN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
5-(3-Methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamine (130 mg, 0.67 mmol, Eq: 1.0), 4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (165 mg, 223 mmol, Eq: 1.1), xantphos (58 mg, 0.1 mmol, Eq: 0.15), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, Eq: 0.075) and cesium carbonate (767 mg, 2.35 mmol, Eq: 3.5) were added to a microwave vial. The vial was capped and purged with argon. Degassed dioxane (4.5 ml) was added to the vial through the septum and the vial was purged again, then backfilled with argon. The reaction was heated at 90° C. overnight in a sand bath. The crude reaction mixture was filtered through celite and purified by chromatography using a gradient of 5% to 25% methanol in DCM with a little added ammonium hydroxide to give 150 mg of product (63.7%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[CH3:36][O:35][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)[CH:22]=[CH:21][N:20]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN1CCNCC1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 80 %

Procedure:
1-Methylpiperazine (89 mg, 0.89 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129 (which may be prepared by the method described for Intermediate 87), 350 mg, 0.89 mmol) and DIPEA (0.186 mL, 1.07 mmol) were suspended in DMA (6 mL) and sealed into a microwave tube. The reaction was heated to 140° C. for 1 h in a microwave and then cooled to r.t. CH3OH was added and an orange solid precipitated from solution. The solid was collected by filtration and was washed with CH3OH and then diethyl ether. The solid was then dried to give the title compound (339 mg, 80%) as an orange solid; 1H NMR: 2.26 (3H, s), 3.06-3.11 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 6.86 (1H, s), 7.13 (1H, t), 7.23-7.29 (2H, m), 7.53 (1H, d), 8.10 (1H, s), 8.32-8.38 (3H, m), 8.81 (1H, s); (signals for 4 protons were not observed and are likely to be obscured under the DMSO peak); m/z: ES+ MH+ 474.56.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]([CH3:12])[CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of 4-bromo-3-((dimethylamino)methyl)phenol (4 g, 17.4 mmol), benzylbromide (2 eq.), and potassium carbonate (3 eq.) in DMF (100 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 1-(5-(benzyloxy)-2-bromophenyl)-N,N-dimethylmethanamine (709) (98%).