Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13](OC)=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].CO>C1COCC1>[F:1][CH2:2][C:3]1[CH:12]=[C:7]([CH:6]=[C:5]([CH2:13][OH:14])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CF)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(CF)c1
Yield: 79.6 %

Procedure:
Dimethyl 5-fluoromethylisophthalate (33) (3.16 g, 14.0 mmol) was dissolved in THF (10.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (638 mg, 16.9 mmol), and then a mixted solution of THF:MeOH (8.8 mL:2.6 mL) slowly dropwise. The reaction mixture was refluxed for 1 hour. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with HCl (1 N, 14 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=5:1 to 2:1) to isolate methyl 3-fluoromethyl-5-hydroxymethylbenzoate (34) (2.21 g, 80%) as white crystals.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].[OH-].[Na+]>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Cc1cccc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 160 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.butyl)-3-azetidinol and 6.7 parts of 2,3-xylenol 0.2 part of sodium hydroxide was added, and the mixture was heated at 160° C. for 24 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed twice with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 50 parts of 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and was made alkaline by addition of 2 N-sodium hydroxide aqueous solution. The solution was cooled and agitated to form crystals. The resulting crystals were dried and recrystallized twice from ether to yield 9.2 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:31])[F:32])[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1C(F)(F)F
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1C(F)(F)F
Yield: 83.2 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (100 mg, 0.44 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-oxo-3-[2-(trifluoromethyl)phenyl]propanoate (250 mg, 0.85 mmol) produced above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (158 mg, 84%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:13])[C:10]#[C:11][CH3:12]>C(#N)C>[CH2:9]([NH:13][C:4](=[N:3][C:1]#[N:2])[S:5][CH3:6])[C:10]#[C:11][CH3:12]
Reactant: CC#CCN
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CC#CCNC(=NC#N)SC

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound B, mp 180°-183°.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]2[C:6]=1[CH:7]1[CH:12]([C:13]2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>N1C=CC=CC=1>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]2[C:6]=1[CH:7]1[CH:12]([C:13]2=[N:2][OH:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1cc(C)c2c(c1O)C(=O)C1CCCCC21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(c1O)C(=NO)C1CCCCC21

Procedure:
7.99 Grams of hydroxylamine hydrochloride was added to a solution prepared by dissolving 17.22 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of pyridine and the mixture was refluxed under heating for 2 hours. Pyridine was distilled off under reduced pressure and the resulting residue was extracted with 300 ml of chloroform. The extract was washed with water 1% hydrochloric acid and then with saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. After the solvent was distilled off, the product was recrystallized from ethanol to obtain 11.56 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone oxime as a mixture of syn-isomer and anti-isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]([NH:13][CH2:14][C:15](=O)[CH3:16])=[O:12])=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[O:12][C:15]([CH3:16])=[CH:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)CNC(=O)c1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)nn2)o1
Temperature: 25 °C

Procedure:
To a solution of 6-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-N-(2-oxopropyl)pyridazine-3-carboxamide (1.2 mmol) form Step 1 in tetrahydrofuran (30 mL) was added Burgess reagent (343 mg, 1.4 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated in vacuo. The resulting crude residue was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([NH2:13])[N:7]=1.[CH2:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][C@@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:13][C:8]1[N:9]=[C:10]([N:26]2[CH2:25][CH2:24][C:23]3([CH2:19][N:20]([C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])[C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22]3)[CH2:28][CH2:27]2)[CH:11]=[C:6]([O:5][CH2:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Br:1])[N:7]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)cc(OCc2ccc(Cl)cc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4Br)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine (300 mg, 1.1 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol), and NaHCO3 (550 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, water, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=CC=CC=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:21])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1C(=O)Cl
Yield: 72 %

Procedure:
5-Chloro-2-methoxybenzoic acid (19 g.) was heated in thionyl chloride 64 ml.) under reflux for 1 hour. Benzene (100 ml.) was then added, and evaporated off under reduced pressure. The solid residue was recrystallized from hexane to give the required product (15 g., 72%) m.p. 59°-60°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8](C)=[CH:7][C:3]=1[C:4]([Cl:6])=[S:5].ClCl.[CH:15]([Cl:18])([Cl:17])[Cl:16]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:15]([Cl:18])([Cl:17])[Cl:16])=[CH:7][C:3]=1[C:4]([Cl:6])=[S:5]
Reactant: Cc1cc(C(=S)Cl)c(Cl)cc1Cl
Reactant: ClC(Cl)Cl
Agent: ClCl
Product: S=C(Cl)c1cc(C(Cl)(Cl)Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-5-methylthiobenzoyl chloride (25 g.; 0.097 mole) in chloroform (1.30 ml.) is cooled in ice water to 20° C. and irradiated with a 200 watt bulb while a slow stream of chlorine is bubbled into the reaction mixture for four hours. The reaction mixture is stirred at 25° C. for 18 hours; then the solvent is removed by distillation at reduced pressure. The 2,4-dichloro-5-trichloromethylthiobenzoyl chloride which remains (14.0 g.; 40%) melts at 79°-81° C. after recrystallization from hexane.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][CH:17]2[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC1(C)COCC(COS(C)(=O)=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COCC(CNc2cccc(Br)n2)O1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
6-Bromopyridin-2-amine (722 mg, 4.17 mmol) was dissolved in 8 mL of anhydrous DMF and cooled to 0° C. NaH (60% in mineral oil, 195 mg, 4.87 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 45 min until bubbling ceased. The solution was cooled to 0° C. again and (6,6-dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (520 mg, 2.32 mmol) in 2 mL of DMF was added. After the addition was completed the solution was warmed to ambient temperature and stirred overnight. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on prep HPLC and the collected fractions were combined, concentrated, basified with Na2CO3 and extracted with EtOAc three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a light yellow oil (270 mg, 39%). LC-MS (m/z): 301.0/303.0 (M+H), retention time=0.86 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([Br:41])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(Br)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 44.9 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (10 ml). Sodium hydride (60 mg) and 2-chloro-5-bromo-pyrimidine (100 mg) were added and the mixture was heated to 75° C. for 48 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (54 mg) as a white powder. LC-MS: tR: 4.23, [M+H]+: 605.90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([CH:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[O:19][CH2:18][CH2:17][O:6]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(C2(C3CCNCC3)OCCO2)cc1Cl
Yield: 51 %

Procedure:
A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.0 g, 3.9 mmol), ethylene glycol (0.65 ml, 11.6 mmol), p-toluenesulfonic acid mono hydrate (1.48 g, 7.8 mmol), and toluene (100 mL) was refluxed through a Dean-Stark trap for 4 h. After concentration, the residue was stirred with ethyl acetate and dilute aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give 4-[2-(3,4-dichlorophenyl)-[1,3]dioxolan-2-yl]piperidine (0.6 g, 1.99 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1ccnc1C(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (3 mg, 0.01 mmol, 8%). LCMS: [M+H]+=335, Rt=1.48 min, 94% purity.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1([CH3:18])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][O:6]1.[OH-].[Na+]>CO.O>[CH3:18][C:5]1([CH2:4][C:3]([OH:19])=[O:2])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][O:6]1
Reactant: COC(=O)CC1(C)OCCC2=C1Cc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CC(=O)O)OCCC2=C1Cc1ccccc12
Reaction time: 8 h

Procedure:
Hydrolysis of this ester to the title compound is effected as follows: The latter ester (11.5 g) is dissolved in 400 ml of methanol and the solution mixed with a solution of 12 g of sodium hydroxide in 100 ml of water. The resulting mixture is kept at room temperature overnight. Methanol is removed by evaporation. The residue is diluted with water. The aqueous solution is extracted repeatedly with ether, and acidified with 6N hydrochloric acid. The resulting precipitate is extracted with ether. The ether extract is dried (MgSO4), filtered and concentrated. The residue is crystallized from benzene to give the title compound, m.p. 179°-180° C, nmr (CDCl3) δ 1.45 (s, 3H), 2.51 (m, 2H), 2.73 (s, 2H), 3.25 (t, 2H), 4.02 (t, 2H), 7.26 (m, 4H), 9.80 (broad, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH:26]3[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cncc(C2CCCN2)c1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCCN3CCCC3c3cccnc3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (Example 1, Step A, 0.400 g, 1.16 mmol), 3-pyrrolidin-2-yl-pyridine (0.345 mL, 2.33 mmol), K2CO2 (0.322 g, 2.33 mmol), and KI (0.019 g, 0.116 mmol) in 23 mL of acetonitrile was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated to give a brown oil. The product was purified by flash column chromatography on silica gel (3% methanol:CH2Cl2) and triturated with diethyl ether/hexanes/CH2Cl2 to give 0.120 g (23.0%) of a light yellow solid: mp 126-127° C.; IR (KBr)3036, 2962, 2793, 1693, 1594, 1454, 1168, 1077 cm−1; 1HNMR (400 MHz, DMSO-d6) δ 1.40-1.52 (m, 1H, NCHCH2CH2CH2), 1.70-1.85 (m, 2H, NCHCH2CH2CH2 & NCHCH2CH2CH2), 2.10-2.18 (m, 1H, NCHCH2CH2CH2), 2.29-2.31 (m, 1H, NCHCH2CH2CH2),2.34-2.42 (m, 1H, NCHCH2CH2CH2), 2.46 (s, 3H, CCH3), 2.71 (t, J=6.35 Hz, 2H, OCH2CH2), 3.38-3.42 (m, 1H, NCHCH2CH2CH2), 3.82 (t, J=5.62 Hz, 2H, OCH2CH2), 5.26 (s, 2H, OCH2Ar), 6.64 (dd, J=8.79, 2.44 Hz, 1H, ArH), 7.17 (t, J=8.55 Hz, 1H, ArH), 7.28 (t, J=7.08 Hz, 3H, ArH), 7.35 (t, J=7.33 Hz, 2H, ArH), 7.46 (d, J=7.81 Hz, 2H, ArH), 7.73 (d, J=7.81 Hz, 1H, ArH), 8.39-8.40 (m, 1H, ArH), 8.51 (s, 1H, ArH), 11.70 (s, 1H, NH); MS(APCI+): m/z 456.2 (MH+). Anal. Calcd for C28H29N3O3: C, 73.79; H, 6.42; N, 9.22. Found: C, 73.42; H, 6.45; N, 9.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21]CC)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 2.0 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate, 10 ml of methanol, and 10 ml of THF was added 10 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The solution was acidified by the addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 1.9 g of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid as a pale yellow crystal.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OC2CCNCC2)nc1
Reaction time: 1.5 h

Procedure:
2-[1-(t-Butyloxycarbonyl)-piperidin-4-yloxy]-5-bromopyridine was stirred in dichloromethane (8 ml). Trifluoroacetic acid (5 ml) was added and stirring continued at room temperature for 1.5 h. Volatile materials were removed in vacuo and the residue was triturated with ether and hexane, then collected by filtration to give the product as a white solid (0.86 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:36]2[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=2)=[CH:8][C:7]=1[CH3:21]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (0.300 g) obtained in Example 10, step A, 2-chloro-5-(trifluoromethyl)pyrimidine (0.108 g), tetrakistriphenylphosphinepalladium (0.0726 g), sodium carbonate (0.200 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.259 g).