Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])O1.[OH2:30]>C1COCC1.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>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[C:18]([O:27][CH3:28])[C:17]=1[CH2:16][S:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:30])[CH:10]=1
Reactant: COc1cc(OC)c(CSc2ccccc2B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(2-(2,4,6-trimethoxybenzylthio)phenyl)-1,3,2-dioxaborolane (1.2 g, 2.9 mmol), 3-lodophenol (0.65 g, 2.9 mmol), Ag2CO3 (0.82 g, 2.9 mmol) and Pd(PPh3)4 (0.16 g, 0.15 mmol) in 6 ml of THF was refluxed in the dark for 12 h. The reaction mixture was poured into H2O and the resulting mixture extracted with ether. The organic layer was washed with brine (3×20 ml) and dried over MgSO4 and concentrated. The residue was purified by silica flash chromatography (40/60, ethylacetate/hexane) to afford 2′-(2,4,6-trimethoxybenzylthio)biphenyl-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[N:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26]([C:23]2[CH:24]=[N:25][C:20]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[CH:21][CH:22]=2)=[O:27])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(-n2cncn2)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2cncn2)nc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg) and 6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxamide. MS (Q1) 377.0 (M)+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:28]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Product: CCCCCCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OCC
Yield: 52.4 %

Procedure:
The title compound (0.52 g, 53%) was prepared as a pale yellow oil from 2-(phenoxazin-10-yl)ethyl methanesulfonate (0.6 g and 1.97 mmol) and ethyl 3-(4-hydroxyphenyl)-2-hexyloxypropanoate (0.70 g, 2.4 mmol) obtained in preparation 8 by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:23])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (80 μL) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(cyano-1-methylethyl)benzoyl chloride as a pale-brown oil. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added an aqueous suspension (60 mL) of sodium hydrogen carbonate (6.05 g, 72.0 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (60 mL) synthesized above under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a colorless powder.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>C(=S)=S>[C:17]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1
Yield: 21.9 %

Procedure:
To a solution of ethyl 2-phenylacetate (A-1) (50.9 g, 305 mmol) in CS2 (220 mL) was added AlCl3 (93.6 g, 702 mmol) at 0˜10° C. over 10 min. After addition, acetyl chloride (30.5 mL, 427 mmol) was added at 0˜10° C. over 10 min. After addition, the reaction mixture was slowly heated to reflux overnight, then poured into ice-cooled 5N HCl solution (600 mL), extracted with EA (200 mL×3). The combined organic phase was washed with water (200 mL), sat. NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, concentrated to afford a brown oil. Recrystallized with PE/acetone (150 mL/20 mL) in refrigerator to afford A-2 as a yellow crystal solid (13.8 g, 19%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]1[CH2:32][O:31][C:10]2([CH2:15][CH2:14][C@H:13]3[C@H:16]4[C@H:25]([CH2:26][CH2:27][C@:11]23[CH3:12])[C:24]2[CH:23]=[C:22]([O:28][CH3:29])C(O)=C[C:19]=2[CH2:18][CH2:17]4)[O:9]1.N1C=CC=CC=1>CO>[C:5]([O:4][C:1]1[C:22]([O:28][CH3:29])=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C:10]3([O:9][CH2:8][CH2:32][O:31]3)[CH2:15][CH2:14]4)[CH2:17][CH2:18][C:19]=2[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Under nitrogen, acetic anhydride (25 mL, 265 mmol) was added to a solution of the ketal (11) (4.5 g, 13.06 mmol) in dry pyridine (25 mL, 310 mmol). The reaction was stirred overnight at room temperature in the dark. After that time, methanol (50 mL) was added and solvents removed in vacuo. The treatment with methanol was repeated and the residue obtained crystallized from methanol to give the pure 3-acetate (12) (4.85 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][C:32]1[C:27]2[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: NCCO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NCCO)ncnc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 2-aminoethanol to obtain the title compound (see Table 1).
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.O>[C:3]([C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:5][CH2:6][C:7]([F:8])([F:9])[F:10])[CH3:11])#[N:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
8.7 g (52.36 mmol) of rac-2-amino-5,5,5-trifluoro-2-methylpentanonitrile from Example 60A were initially charged in 128 ml of tetrahydrofuran/water=9/1, and 22.43 g (162.3 mmol) of potassium carbonate were added. At 0° C., 8.93 g (52.36 mmol) of benzyl chloroformate were added dropwise. Then the mixture was allowed to warm up gradually to room temperature and stirred at room temperature overnight. The supernatant solvent was decanted off, the residue was twice stirred with 100 ml each time of tetrahydrofuran, and then the supernatant solvent was decanted off each time. The combined organic phases were concentrated and the crude product was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient 9/1 to 4/1). 11.14 g of the title compound were obtained (68% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 3-tert-butoxycarbonylmethoxy-benzoic acid methyl ester (1.00 g, 3.75 mmol) in methylene chloride (4 mL), add trifluoroacetic acid (0.50 mL, 6.6 mmol). Stir the mixture overnight at room temperature in an open vial to allow the solvent to escape. Add an additional portion of trifluoroacetic acid (0.50 mL, 6.6 mmol) and stir the reaction mixture for an additional 24 hours. Add an additional portion of trifluoroacetic acid (1.50 mL, 19.8 mmol) and stir the reaction at room temperature for 3 days. Concentrate under reduced pressure to provide 0.750 g (95.0%) of 3-carboxymethoxy-benzoic acid methyl ester as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=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.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: Fc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Sc3ccc(F)cc3)cn2)CC1
Temperature: 110 °C
Yield: 44 %

Procedure:
A stirred solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.924 mmol), 4-fluorobenzenethiol (561 mg, 4.386 mmol), Pd2(dba)3 (267 mg, 0.292 mmol), Xantphos (169 mg, 0.292 mmol) and DIPEA (754 mg, 5.848 mmol) in dioxane (50 mL) was degassed with nitrogen for three times, and then heated at 110° C. for 16 hrs. The reaction mixture was cooled to RT and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (silica gel, 0-20% EtOAc/PE) to afford the title compound as a white solid. (500 mg, yield 44%, purity: 99%). MS (ES+) C19H23FN4O2S requires: 390. found 391 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>C(#N)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Reactant: OCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.34 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.34 g.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([OH:10])=O.[F:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:8]([C:3]2[NH:4][C:5](=[O:7])[NH:6][C:2]=2[CH3:1])=[O:10])=[CH:14][CH:13]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)O
Reactant: O=C(O)c1ccc(F)cc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylic acid (71.0 g, 0.5 mol) and 4-fluorobenzoic acid (105 g, 0.75 mol) are mixed together then covered with polyphosphoric acid (1.6 Kg). The mixture is rapidly heated to 60° C. with stirring, then gradually heated to 110° C. over 2.5 hr with continued stirring. After stirring at ca. 110° C. for an additional 2 hr the mixture is cooled to 60° C. and mixed with crushed ice (3.5 Kg). After all the ice has melted, the mixture is filtered and the solid washed with water. The filter cake is suspended in water (800 mL) and the pH raised to approximately 8 by the gradual addition of 10% aqueous sodium hydroxide solution, and the mixture stirred overnight. The pH is adjusted to 8-9, the solid collected by filtration, washed throughly with water and dried. Recrystallization from isopropanol-water affords the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](OCC2C=CC=CC=2)=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CO)nn2Cc1ccccc1
Yield: 104.4 %

Procedure:
To a solution of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate (17.7 g; 0.05 mol), diethyl ether (100 ml) and tetrahydrofuran (THF) (170 ml) stirred at room temperature was slowly added LiAlH4 (3.8 g; 0.1 mol). Once the addition was complete, the suspension was stirred at reflux for 24 hours. The reaction was stopped by destroying the excess LiAlH4 via addition of water (40 ml) and 5N NaOH (10 ml). The organic phase was separated out and the solvent was evaporated off under reduced pressure. The crude residue obtained was purified by crystallization from 95° ethanol to give 14 g of (1-benzyl-5-methoxy-1H-indazol-3-yl)methanol with a melting point of 97-98° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1C=C(C=[CH:42][CH:43]=1)C=O>>[F:35][C:36]1[CH:13]=[C:8]([CH:9]=[CH:42][CH:43]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cccc(F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s,1H), 7.35-7.30 (m, 1H), 7.21-7.20 (m, 1H), 7.05 (d, J=9.5 Hz, 1H), 6.98-6.93 (m, 1H), 4.83-4.77 (m, 1H), 4.14-4.08 (m, 2H), 3.80-3.77 (m, 1H), 3.64-3.54 (m, 3H), 3.36 (t, J=8.8 Hz, 1H), 3.01 (d, J=9.9 Hz, 1H), 2.84-2.83 (m, 1H), 2.57 (m, 1H), 2.44-2.27 (m, 3H), 1.95-1.83 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 412.4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: BrCCCCCCCBr
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCBr
Yield: 81.6 %

Procedure:
Starting with 0.381 g (1.03 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 2.13 g (8.26 mmol) of 1,7-dibromoheptane, the title compound was obtained as a colorless oil, in 81.6% yield, using the procedure of example 21.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].IC.[C:25](=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cn([C@@H]2CCNC2)c2ccc(I)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
To a solution of (R)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Intermediate 110, 282 mg, 0.68 mmol, 1 equiv.) in THF (7 mL) was added iodomethane (0.0471 mL, 0.75 mmol, 1.1 equiv.) followed by potassium carbonate (378 mg, 2.74 mmol, 4 equiv.). This was stirred at 60° C. for 1 d. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were concentrated to provide (R)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (282 mg, >99%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[NH2:24]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:23]([NH:24][C:11](=[O:12])[C:10]2[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[CH:22]=[C:21]([O:20][CH3:19])[CH:27]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2c(F)cccc2F)cc(OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
5.5 ml (39.2 mmol; 1.2 equivalent) of triethylamine and 4.5 ml (35.9 mmol; 1.1 equivalent) of 2,6-difluorobenzoyl chloride are added to 5 g (32.6 mmol) of 3,5-dimethoxyaniline in solution in 100 ml of anhydrous toluene. The reaction medium is maintained under stirring at 70° C. for 1 hour 30 minutes, then, after returning to ambient temperature, washed with 3 times 50 ml of water. The resulting organic phase is dried over magnesium sulphate then the solvent is evaporated off under reduced pressure. The expected product is obtained in the form of a white powder (8.75 g; yield=97%) used in the following stage without other purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:31])([F:30])[C:24]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]([OH:29])([C:23]([F:31])([F:30])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC1(C(F)(F)F)CCNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(O)(C(F)(F)F)C1
Yield: 47.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 32.4 mg, 169 μmol) to obtain the title compound (28 mg, 47%) as off-white solid, MS (EI): m/e=422.3 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1ccc(Br)cc1C=O
Reactant: OB(O)c1cccs1
Product: COc1ccc(-c2cccs2)cc1C=O

Procedure:
Ex-45A: 2-Methoxy-5-(thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2-methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. 1H NMR (CDCl3) δ 10.49 (s, 1H), 8.07 (d, J=3 Hz, 1H), 7.79 (dd, J=3, 9.0 Hz, 1H), 7.28–7.26 (m, 2H), 7.09–7.06 (m, 1H), 7.02 (d, J=9 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (590 mg, 2.38 mmol) in THF (20 mL) was added 6N HCl (1.2 mL). The reaction was stirred at room temperature for 4 hours and then diluted with EtOAc (50 mL) and washed with water (2×40 mL) and saturated NaHCO3/brine (2×40 mL, 1:1). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded 4-(4-methoxyphenyl)cyclohexanone. 1H NMR (600 MHz, CDCl3) δ 7.15-7.18 (m, 2H), 6.85-6.88 (m, 2H), 3.80 (s, 3H), 2.99 (m, 1H), 2.46-2.54 (m, 4H), 2.17-2.22 (m, 2H), 1.87-1.95 (m, 2H).