Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][N:5](CC(C)C)[C:6]1[CH:11]=CC=C[CH:7]=1)[CH3:3].[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18](C)[CH:17]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:7][C:6]1([CH3:11])[CH2:23][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]1[CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)=CN(CC(C)C)c1ccccc1
Reactant: Cc1cccc(C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)CN1c2ccccc2CC1(C)C
Yield: 71.4 %

Procedure:
A mixture of N-(2-methylprop-2-en-3-yl)-N-isobutylaniline (6.1 g) and zinc chloride (3.9 g) in m-xylene (50 cm3) was heated under reflux for 24 hours before dissolving in dichloromethane and filtering. The dichloromethane solution was washed with water, separated and dried over anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the dichloromethane was separated to leave a crude oil which was purified by elution from silica with a 9:1 mixture of hexane:dichloromethane. The solvent was evaporated to leave 2,2-dimethyl N-isobutylindoline (4.3 g, 71.4%) as a colourless oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@H:28]2[N:32](C(OC(C)(C)C)=O)[C:31]([CH3:41])([CH3:40])[CH2:30][CH2:29]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([C@@H:28]2[CH2:29][CH2:30][C:31]([CH3:40])([CH3:41])[NH:32]2)[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:7][CH:8]=1
Reactant: C[C@@H]1CCc2ncnc(C3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(C3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCC(C)(C)N4)CC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 4M HCl in 1,4-dioxane (0.344 mL) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (26 mg, 0.046 mmol) in 1,4-dioxane (1 mL) at 0° C. The mixture was allowed to warm up and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo. The resulting residue was dissolved in minimal DCM and added to the ether (5 mL) at 0° C. A solid precipitated. The mixture was decanted and dried in vacuo to give (S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)ethanone dihydrochloride as a solid (26 mg, 100%). MS (APCI+) [M+H]+ 467.3. 1H NMR (D2O, 500 MHz) δ 8.96 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 4.60-4.20 (m, 3H), 4.01-3.52 (m, 6H), 3.48-3.05 (m, 4H), 2.85-2.82 (m, 1H), 2.43-2.36 (m, 1H), 1.96-1.86 (m, 5H), 1.32 (s, 3H), 1.1.31 (s, 3H), 1.19 (d, J=7.5 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>CN(C)C=O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)ccn1

Procedure:
Compound 4ff was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 48.7 mg (0.26 mmol) of 2-bromomethyl-6-methyl-pyridine. The crude product was purified by preparative HPLC to yield 15 mg of colorless solid 4ff: LC-MSD, m/z for C23H19N3O2, [M+H]+=370.5, [M+2H]+=371.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.976 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.57 (s, 3H), 2.61 (s, 3H), 5.43 (s, 2H), 6.87 (d, 1H), 7.10 (d, 1H), 7.32-7.48 (m, 4H), 7.53 (t, 1H), 7.59 (t, 1H), 8.41 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([C@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9](COCC[Si](C)(C)C)[N:10]=[CH:11][C:4]=12.Cl>CCO>[CH3:1][N:2]([C@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:3]1[N:8]=[CH:7][N:6]=[C:5]2[NH:9][N:10]=[CH:11][C:4]=12
Reactant: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@H]1CCCNC1
Agent: Cl
Solvent: CCO
Product: CN(c1ncnc2[nH]ncc12)[C@H]1CCCNC1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
To a solution of (S)—N-methyl-N-(piperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (310 mg, 0.85 mmol) in EtOH (7.5 mL), cone. HCl (2.5 mL) was added and the reaction mixture was heated at 60° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (5 mL) and a polymer support carbonate resin was added until the mixture turned basic (Checked by litmus paper). The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the titled intermediate (189 mg, 95%), which was used further without further purification. LC-MS: m/z [M+1]=233.
Reaction SMILES: C([O:4][P:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[NH:22][C:21]3[CH:23]=[C:24]([F:39])[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)=[CH:26][C:20]=3[N:19]=2)[CH:12]=1)(=[O:10])[O:6]C(C)C)(C)C.C[Si](N[Si](C)(C)C)(C)C.Br[Si](C)(C)C>C(Cl)Cl>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:25]2[C:24]([F:39])=[CH:23][C:21]3[NH:22][C:18]([O:17][C:13]4[CH:12]=[C:11]([P:5](=[O:4])([OH:10])[OH:6])[CH:16]=[CH:15][CH:14]=4)=[N:19][C:20]=3[CH:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)OP(=O)(OC(C)C)c1cccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)c1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: O=P(O)(O)c1cccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 13-8 (40 mg, 0.073 mmol) in 3 mL of CH2Cl2 was added hexamethyldisilizane (0.3 mL), followed by bromo trimethylsilane (0.1 mL, 0.74 mmol). The reaction was allowed to stir for 18 h at ambient temperature. The organic solvent was removed in vacuo, followed by the addition of H2O (1 mL). The crude product was sonicated and yielded a white suspension. Solvent was removed in vacuo and the product was dissolved in DMSO (1.5 mL). The product was purified by prepatory HPLC using a 30-80% CH3CN with 0.05% trifluoroacetic acid gradient over 20 minutes. The pure fractions were combined and lyophilized to give the desired title compound 13-9. 1H NMR δ 7.35-7.41 (2H, m), 7.48-7.51 (3H, m), 7.56-7.66 (6H, m), 7.72-7.77 (4H, m); LC-MS: m/e 461(M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CN(C)c1ccnc(I)c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(N(C)C)ccn2)c1
Temperature: 90 °C
Yield: 83.6 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (2.7 g, 11 mmol), 3-methoxyphenylboronic acid (2 g, 13 mmol) and K2CO3 (5.4 g, 39 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated. The crude compound was purified by column chromatography (SiO2, EtOAc) to afford 2.1 g (84%) of the titled compound as a colorless oil, which solidify upon standing. If some impurities remains, the compound can be purified by following the acidic extraction followed by basic recovery as performed before for 2-phenyl-4-dimethylaminopyridine.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([S:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[O:10][C:11]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][C:12]=1[C:13]([O:15]CC)=[O:14])[CH3:5]>O1CCCC1.O>[CH2:4]([S:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[O:10][C:11]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][C:12]=1[C:13]([OH:15])=[O:14])[CH3:5]
Reactant: CCOC(=O)c1cc(F)cnc1Oc1cccc(SCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Lithium hydroxide hydrate (1.37 g, 33 mmol) was added to a solution of ethyl 2-[3-(ethylsulfanyl)phenoxy]-5-fluoronicotinate (4.21 g, 13 mmol) in tetrahydrofuran (50 ml) and water (30 ml). The mixture was stirred for 4 h, then the volatile solvent was removed under reduced pressure and the residue partitioned between diethyl ether and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:acetic acid (95:5:0.5) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (3.45 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=[O:21])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[OH:7][B:5]1[C:4]2[CH:8]=[CH:9][C:10]([CH:12]=[O:21])=[CH:11][C:3]=2[C:2]([CH3:13])([CH3:1])[O:6]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccc2c(c1)C(C)(C)OB2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2ccc(C=O)cc21
Temperature: 25 °C
Yield: 412.8 %

Procedure:
To a solution of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (27 mg, 0.153 mmol) in CCl4 (2 mL) at rt was added benzoyl peroxide (3.7 mg, 0.0153 mmol) followed by NBS (60 mg, 0.337 mmol). The reaction mixture was heated under reflux for 12 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH of 3 and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (12 mg; yield 41%) as white solid. 1H NMR (400 MHz, CDCl3): δ 10.12 (s, 1 H), 7.88 (s, 2 H), 7.80 (s, 1 H), 1.62 (s,6 H) ppm.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:15](=O)[C:14]([C:17]([OH:19])=[O:18])=[CH:13][NH:12][C:11]1=[O:20].Cl>O1CCOCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]3[C:11](=[O:20])[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[C:15]3[S:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(-n2c(=O)[nH]cc(C(=O)O)c2=O)c(S)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12

Procedure:
29.4 g. 1-(2-Mercapto-4-methoxyphenyl)-5-carboxypyrimidine-2,6-dione are boiled for 6 hours in 300 ml. of a semi-concentrated dioxane solution of hydrochloric acid. The 7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid which is thereby formed can be obtained in practically quantitative yield by suction filtration of the hot solution. The physical data of the product agree with those of the compound prepared according to Variant I.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:16]([O:18]CC)=[O:17])[C:5]([CH3:15])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][CH:7]2[OH:14].[OH-].[K+]>C(O)C.[Zn]>[OH:14][CH:7]1[C:6]2[C:11](=[CH:2][CH:3]=[C:4]([C:16]([OH:18])=[O:17])[C:5]=2[CH3:15])[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2(=O)=O
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc2c1C(O)CCS2(=O)=O
Temperature: 50 °C
Yield: 143.4 %

Procedure:
10.0 g (31.3 mmol) of the 8-chloro-6-ethoxycarbonyl-4-hydroxy-5-methylthiochroman-1,1-dioxide obtained in the above step (7) was dissolved in 30 ml of ethanol, and 50 ml of a 16% potassium hydroxide aqueous solution and 6.1 g (93.3 mmol, 3.0 equivalents) of a zinc powder were added. The mixture was stirred under heat at 50° C. for 3 hours. After the completion of the reaction, the zinc powder was filtered off. While the reaction mixture was cooled, a 2N hydrochloric acid aqueous solution was added until the mixture had a pH of 1. Then, the mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off to give 11.5 g (yield 100%) of 4-hydroxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)=[CH:19][N:18]=2)[CH2:8]1>CO.[Pd]>[Cl:3][C:4]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:8]1
Reactant: [H][H]
Reactant: O=C(CCc1ncc(-c2ccc([N+](=O)[O-])cc2)cn1)NCC1CCN(Cc2cccc(Cl)c2Cl)C1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cnc(CCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
Hydrogen gas (balloon pressure) was introduced into a vessel containing Pd/C (10%, 100 mg, 0.1 mmol, 0.05 equiv.) in a solution of N-[1-(2,3-dichlorobenzyl)-pyrrolidin-3-(RS)-ylmethyl]-3-[5-(4-nitrophenyl)pyrimidin-2-yl]propionamide (1.0 g, 2.2 mmol) in methanol (30 mL). After 1.5 h, the reaction was terminated by purging with N2 and the reaction mixture was filtered through celite® and concentrated. The yellow residue was dissolved in ethyl acetate, then taken into the aqueous phase using 1 M hydrochloric acid. The aqueous phase was basified to pH 11, then extracted thoroughly with ethyl acetate. The organic fractions were combined and washed with brine, then dried sodium sulfate and concentrated to afford N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-3-[5-(4-aminophenyl)pyrimidin-2-yl]propionamide as a yellow crystalline solid (630 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=O)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.CSC.CO>C1COCC1>[CH3:10][N:8]([CH2:6][C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:13]([F:14])([F:16])[F:15])[CH3:9]
Reactant: CN(C)C(=O)c1ccc(N)cc1C(F)(F)F
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL) stirred under a N2 atmosphere at 20° C. was added BH3.DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. To the solution was added MeOH, then concentrated in vacuo to give the crude product. The crude material was purified by silica column chromatography (DCM/MeOH=30:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.4) were combined and concentrated to yield light yellow oil of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:37][C:38]([O:40]CC)=[O:39])=[O:5])C.[OH-].[Na+].CCO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:38]([CH2:37][C:7]1[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=1)=[CH:11][CH:10]=2)([OH:40])=[O:39]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)-2-ethoxycarbonylmethyl-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid ethyl ester (80 mg, 0.13 mmol, see step (a) above), NaOH (aq, 1 M, 1.1 mL), EtOH (0.5 mL) and THF (0.5 mL) was stirred at 100° C. for 9 h, cooled, diluted with H2O and acidified to pH 5 with citric acid (aq, 1 M). The precipitate was collected, washed with H2O and Et2O to give the title compound, 30 mg (42%), mp 203° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[C:25]([F:32])=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:32][C:25]1[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=1
Reactant: Nc1c(F)ccc(O)c1F
Reactant: O=C(O)c1cccc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1c(F)ccc(O)c1F)c1cccc(-c2cccc(F)c2)c1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a stirred solution of 3-(3-fluorophenyl)benzoic acid (430 mg, 1.99 mmol, 1.1 eq), in CH2Cl2 (10 mL) and DMF (0.15 mL) at 0° C. was added (COCl)2 (760 mg, 5.97 mmol, 3.3 eq) dropwise. The reaction was stirred for 2 h, then the solvent removed. The residue dissolved in THF (6 mL) and added to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (262.5 mg, 1.81 mmol, 1.0 eq) and NaHCO3 (760 mg, 9.05 mmol, 5 eq) in THF (6 mL) at 0° C. The reaction was stirred for 3 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was crystallised from petroleum ether:EtOAc 3:1 to give the title compound (310 mg, 50%). Evaporation of the filtrate provided a further 180 mg of impure material.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[S:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=S)c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCO3
Reaction time: 4 h

Procedure:
A solution of 30 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)thiourea, 27.6 mls. of benzaldehyde, and 2 mls. of methanesulphonic acid in 500 ml. of toluene is refluxed under a Dean Stark water separator for 4 hours, during which 2 ml. water is collected. The filtered solution is then evaporated to yield a powder. This product is recrystallized from dioxane and water to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione, m.p. 215°-218°C.
Reaction SMILES: [N:1]1([C:6]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[C:13]1([CH:11]([C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9][CH2:10]2)[NH2:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCCC2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: NC(c1ccccc1)C1(N2CCCC2)CCCC1
Yield: 56 %

Procedure:
The title compound (0.55 g, 56%) was prepared from 1-(1-pyrrolidinyl)cyclopentane carbonitrile D9 (0.66 g, 4 mmol), and phenyllithium in dibutylether (2.4 ml of a 1.8M solution; 4.4 mmol) in THF (4 ml), followed by reaction with sodium borohydride (0.456 g, 12 mmol) in methanol (4 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.41 (1H, m), 1.17 (1H, m), 1.35 (2H, m), 1.60 (2H, m), 1.73 (5H, m), 1.84-2.02 (3H, m), 2.64-2.74 (4H, m), 4.27 (1H, s), 7.21-7.31 (3H, m), 7.48 (2H, m).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:36][CH:33]2[CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CC4)ncnc32)[C@]1(C)F
Yield: 62 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added cyclopropylamine (about 0.296 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.13 g) as a colorless gummy mass. Yield: 62%;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:11][C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:14]
Reactant: CCOC(=O)CCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCCOC(=O)Cl
Temperature: 0 °C
Yield: 179.1 %

Procedure:
Ethyl 5-hydroxypentanoate (1.12 g, 7.66 mmol) was dissolved in 25 mL of methylene chloride, triphosgene (772 mg, 0.34 equivalent), and pyridine (0.743 mL, 1.2 equivalent) were sequentially added while stirred at 0° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added, and extraction operation (methylene chloride) was performed. The separated organic layer was washed using an aqueous saturated sodium chloride solution, and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product. This was purified by column chromatography (ethyl acetate:n-hexane=1:10) to obtain the title compound (972 mg) having the following physical property values.