Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:18]1[N:23]2[N:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:22]2[N:21]=[C:20]([CH3:30])[CH:19]=1.CN(C)C=O>O1CCOCC1>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:18]2[N:23]3[N:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:22]3[N:21]=[C:20]([CH3:30])[CH:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCn1ccnc1
Reactant: Cc1cc(Cl)n2ncc([N+](=O)[O-])c2n1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(NCCCn2ccnc2)n2ncc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
2.88 g of 3-imidazol-1-ylpropylamine and 2.33 g of triethylamine in 20 cc of dioxane were introduced into a 100 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a condenser. 4.5 g of 7-chloro-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine in solution in 20 cc of dioxane and 5 cc of dimethylformamide were added dropwise. After 2 hours of stirring at room temperature, the precipitate was filtered off. It was washed with diisopropyl ether and dried under vacuum. This gave 7.2 g of crude product. This product was taken up under reflux in 28 cc of water, then filtered off at room temperature. This operation was repeated a second time. The product was washed with ethanol and with diisopropyl ether. This gave 4.1 g of (3-imidazol-1-ylpropyl)(5-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-yl)amine in the form of a beige powder, after drying under vacuum over phosphoric anhydride, with a yield of 65%.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3]([O:5][N:6]=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][C:14](O)=[O:15])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl>[Cl:1][CH:2]([Cl:17])[C:3]([O:5][N:6]=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][C:14]([Cl:19])=[O:15])=[O:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of 2-dichloroacetoxyiminophenylacetic acid (syn-isomer) (0.276 g) in methylene chloride (10 ml) was added phosphorus pentachloride (0.208 g) and the mixture was stirred for one hour at room temperature, during which time solution took place. After removal of solvent under reduced pressure, benzene was evaporated from the residue, and the resulting oil freed from solvent under vacuum, giving 2-dichloroacetoxyiminophenylacetyl chloride (syn-isomer) (0.29 g., 100%), νmax. (liquid film) 1770 cm.-1 (COCl and CO2R).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[SH:13])[C:6]([O:8][CH3:9])=[O:7].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.II.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1.CO>[N:16]1[C:17]2[NH:2][C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]=3[S:13][C:18]=2[CH:19]=[CH:20][CH:15]=1
Reactant: Clc1ccccn1
Reactant: COC(=O)c1ccc(S)c(N)c1
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)Nc1ncccc1S2
Temperature: 100 °C

Procedure:
150 g of methyl 3-amino-4-mercaptobenzoate hydrochloride was suspended in 200 ml of diphenyl ether and heated to 100° C. After dropping 2-chloropyridine thereinto, 10.3 g of iodine was further added and the resulting mixture was reacted at 200° C. for 3 hours. After adding 20 ml of sulfuric acid and 300 ml of methanol at room temperature, the resulting mixture was heated under reflux for 3 hours. Then the reaction mixture was brought back to room temperature and poured into a cold saturated aqueous solution of sodium bicarbonate. Next, it was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The extract was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.3 g of the title compound as yellow crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: BrCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
As shown in the above Reaction Scheme 1, 1,5-dibromopentane is reacted with potassium phthalimide in a suitable solvent to give N-(5-bromopentyl)phthalimide (2). The compound (2) is reacted with pyrrolidine in the presence of potassium carbonate and sodium iodide to give N-(5-pyrrolidin-1-ylpentyl)phthalimide (3). The compound (3) is reacted with hydrazine to provide 5-(pyrrolidin-1-yl)pentylamine (4). The compound (4) is reacted with di-t-butyl dicarbonate to give t-butyl (5-pyrrolidin-1-ylpentyl) carbamate (5). Then, the compound (5) is reacted with lithium aluminum hydride in a suitable solvent to give N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33].CCOCC>ClCCl>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]1[C:31]([O:32][CH3:33])=[O:34]
Reactant: COC(=O)C1CCNC(Cc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(C(F)(F)F)c2)C1
Yield: 85.3 %

Procedure:
Methyl 2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylate (6.0 g, 19.91 mmol) was dissolved in DIPEA (6.94 mL, 39.83 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (2.258 g, 23.90 mmol) was added dropwise. Ether was added and the reaction mixture was washed with 1 M HCl and Na2CO3 (aq). The organic layer was dried over MgSO4, filtered through celite and the solvent was evaporated to yield dimethyl 2-(3-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (6.1 g, 85%).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]2[C:65]=1[CH2:64][CH2:63][CH2:62]2>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:56][C:57]3[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]4[C:65]=3[CH2:64][CH2:63][CH2:62]4)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)CC(C)c1ccc(N)c2c1CCC2
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)c2c1CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.6 %

Procedure:
A mixture of 2-(2-o-tolylamino-benzoxazol-6-yl)acetic acid (0.398 g, Reference Example 2), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.59 g) and diisopropylethylamine (0.24 g) in dimethylformamide was stirred at room temperature for 10 minutes and then treated with a solution of ethyl 3-[7-amino-indan-4-yl]-butanoate hydrochloride (0.4 g, Reference Example 5) in dimethylformamide. After shaking and then allowing to stand at room temperature for 16 hours the reaction mixture was evaporated under high vacuum. The residual red oil was dissolved in ethyl acetate and the solution was washed with 5% aqueous sodium bicarbonate, then with water, then dried over sodium sulfate and then evaporated to give the title compound (0.754 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:40])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 155.8 %

Procedure:
A suspension of 9.8 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one and 5.5 g of Lawesson reagent in 200 ml of toluene is stirred at 40°-43° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroformmethanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 9.6 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 180°-182° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([CH3:11])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc(Br)cn2ccnc12
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Yield: 75.2 %

Procedure:
Prepared from 6-bromo-8-methyl-imidazo[1,2-a]pyridine (example C.20 step 1) (7.0 g, 33 mmol) and commercially available 4-chlorophenylboronic acid (6.005 g, 36 mmol) as described in example C.20 step 2. Obtained the title compound as a white solid (6.02 g, 75%). MS (ISP) 243.2 [(M+H)+], 245.1 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>O1CCOCC1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:7][C:6]=2[CH:11]=1
Reactant: COc1cc2sc(N)nc2cc1Br
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-6-methoxybenzo[d]thiazol-2-amine V (2.0 g, 7.72 mmol) in 1,4-dioxane (20.0 mL) was added ethylisocyanate (3.0 mL, 38.60 mmol) and heated the resulting reaction mixture to 80° C. for 16 h. After the completion of the reaction (TLC monitoring), 1,4-dioxane was distilled off followed by co-distillation with n-hexane (2 times). The residue was then stirred with water at 90° C. for 2 h followed by filtration to obtain the desired product that was further washed with hot water and then dried. The residue was finally washed with ether to obtain the desired product (2.10 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, J=7.20 Hz, 3H), 3.17 (quintet, J=6.80 Hz, 2H), 3.86 (s, 3H), 6.65 (br s, 1H), 7.68 (s, 1H), 7.80 (s, 1H) and 10.67 (br s, 1H). MS: 330.08 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=364.1, tR (minutes, Method F)=2.64. [α]D20=+41.3 (c=1.5 mg/mL,CHCl3)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].[NH2:17][C:18]1[N:23]=[C:22](S(CC2C=CC=CC=2)=O)[N:21]=[C:20]([C:33]2[C:34]([Cl:44])=[CH:35][C:36]([Cl:43])=[C:37]([CH:42]=2)[O:38][CH2:39][C:40]#[N:41])[N:19]=1>CN(C)C=O>[NH2:17][C:18]1[N:23]=[C:22]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[N:21]=[C:20]([C:33]2[C:34]([Cl:44])=[CH:35][C:36]([Cl:43])=[C:37]([CH:42]=2)[O:38][CH2:39][C:40]#[N:41])[N:19]=1
Reactant: N#CCOc1cc(-c2nc(N)nc(S(=O)Cc3ccccc3)n2)c(Cl)cc1Cl
Reactant: COc1ccccc1S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1nc(N)nc(-c2cc(OCC#N)c(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Triethylamine (12 μL) and 2-methoxybenzenethiol (12 mg) were added in succession to a solution of the above-described [5-(4-amino-6-phenylmethanesulfinyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenoxy]-acetonitrile (12 mg) in dimethylformamide (0.5 mL). The mixture was stirred at room temperature for 8 hours. After dilution with ethyl acetate (7 mL), the mixture was washed twice with water and once with brine. The mixture was pre-dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=7:3) to give {5-[4-amino-6-(2-methoxy-phenylsulfanyl)-[1,3,5]triazin-2-yl]-2,4-dichlorophenoxy}-acetonitrile as white solid (10 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25](OCC)=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH2:30][CH:31]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1>C(O)C>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]([NH:30][CH:31]3[CH2:35][CH2:34][NH:33][CH2:32]3)=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCOC(=O)c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(C(=O)NC4CCNC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a suspension of ethyl 5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.34 mmol) in ethanol (2 mL), tert-butyl 3-aminopyrrolidine-1-carboxylate (49.1 mg, 0.26 mmol) was added and the resulting mixture heated under reflux overnight. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in CH2Cl2 (2.0 mL) and TFA (400 μL) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was passed through a bicarbonate cartridge and the filtrate concentrated in vacuo. The residue was passed through a TsOH cartridge eluting the product with 2M Ammonia in methanol (5 mL). The solid was triturated form acetonitrile to give the product as a yellow solid (44.94 mg, 41%); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, 6H), 1.75 (s, 1H), 2.00 (d, 1H), 2.73-2.78 (m, 2H), 2.94 (s, 1H), 2.95 (dd, 1H), 3.47 (t, 1H), 4.40 (br s, 1H), 7.85 (br s, 2H), 7.98 (d, 2H), 8.32-8.34 (m, 2H), 9.09 (s, 1H) and 9.46 (d, 1H) ppm; MS (ES+) 458.22
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[CH3:16].CI.[C:19]([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[CH3:19][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:11])([CH3:12])[CH3:13])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([CH3:16])[CH:4]=1
Reactant: Cc1cc(C(=S)NC[Si](C)(C)C)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(C)c1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 4-bromo-3-methyl-N-trimethylsilanylmethyl-thiobenzamide (5.00 g, 15.8 mmol) in THF (30 mL) was added methyl iodide (1.97 mL, 4.49 g, 31.6 mmol) and Cs2CO3 (10.3 g, 31.6 mmol) at −5° C. After 1 h at this temperature, the mixture was allowed to reach room temperature and stirred over night. Water was added and the mixture was extracted three times with MTBE. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by filtration over a short plug of silica gel to give the title compound (4.4 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[F:28])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[F:28])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
Benzyloxycarbonyl chloride (710 mg) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-fluorobenzoic acid hydrochloride (610 mg) and sodium hydroxide (390 mg), and the mixture was stirred at room temperature for 4 hours. After the reaction, conc. hydrochloric acid was added to the reaction mixture to make the same acidic, and the mixture was extracted with chloroform. The mixture was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 520 mg of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[C:28]([O:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26])(=[O:30])[CH3:29]
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC(C)c1ncnc(Cl)c1I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-acetoxy-ethyl)-5-iodopyrimidine (1.7 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][NH:6][CH2:7][C:8]#[CH:9].[ClH:10]>C(O)C>[ClH:10].[CH3:3][CH:2]([N:6]([CH2:7][C:8]#[CH:9])[CH3:5])[CH3:4]
Reactant: CC(C)Br
Reactant: C#CCNC
Agent: Cl
Solvent: CCO
Product: C#CCN(C)C(C)C
Yield: 16 %

Procedure:
2-Bromopropane (3.08 g, 25 mmoles) and N-methylpropargylamine (3.45 g, 50 mmoles) in absolute ethanol (50 mL) were heated at reflux for 48 h. On treatment of the ethereal solution of the free base with ethanolic hydrochloride acid, an oil first separated, and then white needles subsequently precipitated very slowly from the supernatant (16% yield of white needles, recrystallized from methanol-ether), m.p.=155°-156° C. The oil and the needles gave identical mass spectra.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCC(=O)Cl
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and propionyl chloride were converted to l-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridin-6-yl)propan-1-one as a white solid (35 mg, 63%): mp 182-187° C.; 1H NMR (500 MHz, DMSO-d6) δ13.15-13.10 (m, 0.25H), 12.87 (br s, 0.75H), 7.76-7.72 (m, 1H), 7.51-7.49 (m, 1H), 4.85-4.83 (m, 1H), 4.68-4.57 (m, 3H), 3.69 (s, 0.5H), 3.63 (s, 1.5H), 3.15-3.13 (m, 2H), 2.79-2.77 (m, 1H), 2.68-2.55 (m, 2H, partially merged with DMSO peak), 2.46-2.38 (m, 2H), 1.76-1.71 (m, 4H), 1.02 (t, J=7.5 Hz, 3H); ESI MS m/z 471 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[O:8][C:9](=[O:22])[CH:10]([NH:19][CH:20]=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl.O>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([C:9]([OH:8])=[O:22])[N:19]=[CH:20]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
Oxalyl choride (5.7 mL) was added dropwise to a solution of 3-(4-chlorophenyl)-2-formylamino-propanoic acid methyl ester (14.5 g, 60 mmol) in CH2Cl2 (400 mL) at room temperature. After stirring for 0.5 hour, ferric chloride (11.7 g) was added and the mixture was stirred for 48 hours. The reaction mixture was diluted with water (500 mL). The organic layer was separated, and the aqueous layer was re-extracted with CH2Cl2 (2×300 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was dissolved in MeOH (400 mL), sulfuric acid (20 mL, 98%) was added and the mixture was heated under reflux for 48 hours. After cooled to room temperature, the reaction mixture was diluted with 5% sodium bicarbonate solution (1 L). The organic layer was separated, and the aqueous layer was re-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/3) and afforded the title compound (3.1 g, 23.3% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): 9.26 (s, 1H), 8.51 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.73 (dd, J=1.8 and 8.7 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-]#N.[Na+].CS(C)=[O:19]>>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][OH:19])=[CH:4][C:5]=2[O:9]1
Reactant: CS(C)=O
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Agent: [C-]#N
Agent: [Na+]
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole (117.6 g, crude from last step) and NaCN (84 g, 1.7 mmol) in DMSO (800 mL) was stirred for 2 h at 25° C. The reaction, mixture was poured into ice and extracted with EtOAc (500 mL×3). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo to give crude product which was purified by column chromatography (P.E./EtOAc 10:1) to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (77.8 g, 66%), 1H NMR (300 MHz , CDCl3) δ 7.06-7.07 (m, 3H), 3.75 (s, 2H).