Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH:6]1[CH:10]([NH2:11])[N:9]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:8]=[CH:7]1)=[O:5])C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26](Cl)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][N:9]([CH:12]4[CH2:13][CH2:14][S:15][CH2:16][CH2:17]4)[C:10]=3[N:11]=[C:26]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1C=NN(C2CCSCC2)C1N
Reactant: Fc1ccccc1C(Cl)=Nc1ccc(Br)cc1
Product: O=c1c2cnn(C3CCSCC3)c2nc(-c2ccccc2F)n1-c1ccc(Br)cc1

Procedure:
5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 5-amino-1-(tetrahydro-thiopyran-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester and N-(4-bromo-phenyl)-2-fluoro-benzimidoyl chloride by following the procedure described in example 2. The crude is purified by preparative LC/MS to provide the titled compound 5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid. HPLC-MS calculated for C22H18BrFN4OS (M+H+): 485.0. Found: 485.0.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:17][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]1[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C=C>CO.C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH2:38]([O:37][C@@H:6]1[C@@H:5]([OH:4])[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:18]([CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:17][C@H:7]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](O)[C@H]2OCc2ccccc2)cc1
Yield: 94 %

Procedure:
Compound 9 (2.67 g, 4.49 mmol) was dissolved in a mixture of anhydrous methanol and toluene (21 mL, v/v 3:1) and reacted with PdCl2 (˜100 mg) under nitrogen and at room temperature. After 4 hours of reaction, the reaction mixture was filtrated over a pad of Celite and the solvents were evaporated. Purification of the residue by chromatography on silica gel (ethyl acetate-petroleum ether, v/v 1:4) afforded 10 as white crystals in 94% yield (2.35 g). mp=84-86° C.; [αD]24 =−11° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3): δ3.66-3.73 (m, 3H, H-5, H-6a and H-6b), 3.74 (t, 1H, J2,3 9.5 Hz, J3,4 2.9 Hz, H-3), 3.76 (s, 3H, OMe), 3.83 (dd, 1H, J1,2 7.7 Hz, H-2), 3.90 (d, 1H, J4,5<1.5 Hz, H-4), 4.44, 4.49, 4.66, 4.78, 4.81 and 5.05 (6 d, 1H each, JA,B 11.8 Hz, CH2Ph), 4.84 (d, 1H, H-1), 6.78 and 7.02 (2 d, 2H each, C6H4), 7.22-7.40 (m, 15H, 3C6H5). Anal. Calcd for C34H36O7 (556.7): C 73.36, H 6.52; found: C 72.96, H 6.63.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21](=[O:33])[C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:31])=[CH:24][C:23]=1[OH:32])[CH2:15]2)(C)(C)C.[ClH:35]>CCOC(C)=O>[ClH:35].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:31])=[CH:24][C:23]=1[OH:32])=[O:33])[CH2:15]2
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3C2)c(O)cc1O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCCN)cc3C2)c(O)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {3-[2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yloxy]-propyl}-carbamic acid tert-butyl ester (Example 46) (1 g) in EtOAc (10 ml) was treated with a saturated solution of HCl in EtOAC (20 ml) then stirred at room temperature for 2 hours. The reaction mixture was evaporated and re-evaporated with ethanol (×3). The title compound was isolated as a cream foam (840 mg). 1H NMR (DMSO-d6) 10.05 (1H, br s), 9.60 (1H, s), 7.88 (3H, br s), 7.30-7.18 (1H, m), 7.05 (1H, s), 7.00-6.85 (2H, m), 6.42 (1H, s), 4.75 (2H, br s) 4.70 (2H, br s), 4.05 (2H, t), 3.10 (1H, m), 3.00-2.95 (2H, m), 2.00 (2H, tt), 1.15 (6H, d). MS: [M+H]+ 371.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccccc3O2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccccc3O2)cc1
Reaction time: 6 h
Yield: 9.3 %

Procedure:
To a solution of (2R)-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (1.70 g, 55.00 mmol) in ethanol (100 mL) is added palladium on carbon (10 wt. %, 0.17 g) and the reaction mixture is shaken under an H2 atmosphere (50 psi) for 6 hours. The reaction mixture is filtered (celite) and the solvent removed in vacuo to provide (2R)-3,4-dihydro-2H-chromen-2-ylmethyl 4-methylbenzene-sulfonate (1.62 g, 95%) as a colorless oil which crystallizes upon standing. [α]D25=−52.69 (c 10.06 in methanol, >97% ee); Rf=0.60 (silica, ethyl acetate:hexanes 2:3); Anal. Calcd. for C17H18O4S: C, 64.13; H, 5.70. Found: C, 63.90; H, 5.71.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[CH:8][CH2:9][CH3:10])[C:4]([F:7])([F:6])[F:5].[OH2:13]>>[F:1][C:2]([F:11])([F:12])[C:3]([OH:13])([CH2:8][CH2:9][CH3:10])[C:4]([F:6])([F:5])[F:7]
Reactant: CCC=C(C(F)(F)F)C(F)(F)F
Reactant: O
Product: CCCC(O)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1-trifluoro-2-pentanol may be prepared by fluorinating commercially available 2-pentenal to form 1,1,2,3-tetrafluoropentane which may then be dehydrogenated to form 1,1-difluoro-1-pentene. CF3 may then be reacted with the 1,1-difluoro-1-pentene to form 2-trifluoromethyl-1,1,1-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,1-trifluoro-2-pentene. The 2-trifluoromethyl-1,1,1-trifluoro-2-pentene may then be reacted with water to form 2-trifluoromethyl-1,1,1-trifluoro-2-pentanol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([CH:29]([CH2:31][CH3:32])[CH3:30])[CH:22]=2)=[C:15]([Cl:33])[CH:14]=1)[CH2:7][C:8]([O:10]CC)=[O:9])C.B(Br)(Br)Br>C(Cl)Cl>[CH:29]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[OH:27])[O:20][C:16]1[C:15]([Cl:33])=[CH:14][C:13]([N:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][C:4]([OH:34])=[O:3])=[CH:18][C:17]=1[Cl:19])([CH2:31][CH3:32])[CH3:30]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(C)c1cc(Oc2c(Cl)cc(N(CC(=O)O)CC(=O)O)cc2Cl)ccc1O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonylmethyl-amino}-acetic acid ethyl ester (12.5 g, 0.02 mol) in CH2Cl2 (250 mL) was cooled to −60° C. under nitrogen atmosphere. To that 1M BBr3 solution (122 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25° C. over 5 h. then diluted with more CH2Cl2 (250 mL) and quenched with H2O. After stirring at 20-25° C. for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (chloroform:methanol) gradient elution from 95:5 to 90:10 to give pure {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-carboxymethyl-amino}-acetic acid (6.8 g, 63% yield)
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].Cl>C(O)C.O>[CH2:18]([C:13]1[C:14]([C:16]#[N:17])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=2)[C:12]=1[CH3:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(C#N)cn(-c2ccc(C(=O)OCC)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1c(C#N)cn(-c2ccc(C(=O)O)cc2)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A suspension of 4-(3-butyl-4-cyano-2-methylpyrrole-1-yl)benzoic acid ethyl ester (0.030 g) and lithium hydroxide mono hydrate (0.041 g) in ethanol (2 mL) and water (1 mL) was stirred at 50° C. for 2 hours. To this reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and this mixture was stirred at room temperature for 30 minutes. This reaction mixture was extracted with ethyl acetate, and this organic layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.027 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(N)cc3)ccc(OC)c2OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(NS(C)(=O)=O)cc3)ccc(OC)c2OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methanesulphonylchloride (0.41 ml) was added to a stirred solution of the Intermediate (a) (2.74 g) and triethylamine (0.74 ml) in dry dimethylformamide. The solution was stirred at room temperature for 10 hours.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24].[Na].[Cl-].[Na+]>ClCCl.O.ClCCl.CC(C)=O>[CH3:8][S:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCc1cccn1CCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)OCCCn1cccc1CC#N
Yield: 76 %

Procedure:
Triethylamine (31 g, 0.306 moles) and methanesulfonyl chloride (32 g, 0.279 moles) are successively added to a stirred and cooled (-8°) solution of 1-(3-hydroxypropyl)pyrrol-2-acetonitrile (38.1 g., 0.232 moles) in dichloromethane (250 ml.), maintained in an atmosphere of nitrogen, at a rate such that the reaction temperature did not exceed 0°. After a further 1 hour at this temperature (t.l.c. silica gel, dichloromethane-acetone, 95:5), saturated sodium becarbonate solution (4.4 ml.), saturated sodium chloride solution (45 ml.) and water (50 ml.) is added. The mixture is stirred for 5 min., the organic phase is separated, and combined with the dichloromethane extracts (2×100 ml.) of the aqueous phase. The extract is washed successively with saturated sodium bicarbonate solution (25 ml.), saturated sodium chloride solution (50 ml.) and water (50 ml.), and then dried over sodium sulfate. The solvent was removed in vacuo and the residual oil (77 g) is purified by chromatography on silica gel to give 42.7 g of 1-(3-methansul-fonyloxypropyl)pyrrol-2-acetonitrile (Formula (XVIII) where n is 1), (76%) was contained in the fraction eluted with hexane-dichloromethane (90:10). This product has the following physical characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH2:34][CH2:33][C@@H:9]3[S:10](=[O:32])(=[O:31])[C:11]([CH3:30])([CH3:29])[C:12]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][C@:8]3([CH2:36][F:37])[C:6]=2[CH:7]=1.[C:38]([C:40]1[CH:41]=[C:42]([CH3:49])[C:43]([C:46](O)=[O:47])=[N:44][CH:45]=1)#[N:39].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:38]([C:40]1[CH:41]=[C:42]([CH3:49])[C:43]([C:46]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:35][CH2:34][CH2:33][C@@H:9]4[S:10](=[O:32])(=[O:31])[C:11]([CH3:29])([CH3:30])[C:12]([N:14]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[N:13][C@:8]4([CH2:36][F:37])[C:6]=3[CH:7]=2)=[O:47])=[N:44][CH:45]=1)#[N:39]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(CF)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@H]1CCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50-mL round-bottomed flask, tert-butyl N-[(4aS,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (102 mg, 0.188 mmol), 5-cyano-3-methylpicolinic acid (36.6 mg, 0.226 mmol), Hunig's base (0.043 mL, 0.245 mmol), and 1-propanephosphonic acid cyclic anhydride (0.120 mL, 0.188 mmol) were added then dissolved in DCM (5 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then diluted with saturated NaHCO3 and extracted with EtOAc (15 mL). The organic extract was washed with water, brine (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give tert-butyl N-[(4aS,11bS)-10-[(5-cyano-3-methyl-pyridine-2-carbonyl)amino]-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate as a white solid that was used without further purification. MS m/z=708.0 (M+Na).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14](O)=[O:15].C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+].OP(O)(O)=O>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14][OH:15]
Reactant: O=C(O)C=Cc1ccc2ccccc2c1Br
Agent: COC(=O)Cl
Agent: O=P(O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: OCC=Cc1ccc2ccccc2c1Br
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a solution of Example 3B (4.66 g, 16.9 mmol) and triethylamine (2.70 mL, 19.4 mmol) in THF (25 mL) at −20° C. was added methyl chloroformate (1.60 mL, 10.3 mmol), and the resulting solution was stirred for 15 minutes. This solution was then added to sodium borohydride (1.92 g, 50.6 mmol) in water (10 mL) at 0° C., stirred at room temperature for 2 hours, acidified with 0.5 M H3PO4, and extracted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgSO4), filtered, and concentrated to provide 2.10 g (47%) of the desired compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:28]=2)[CH3:22])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]
Reactant: CC(N)c1ccc(F)c(NC(=O)C2CC2)c1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 150 °C

Procedure:
To a 10-ml microwave reaction vessel was added 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32, 431 mg, 1.65 mmol), N-[5-(1-aminoethyl) -2-fluorophenyl]cyclopropanecarboxamide (Method 69, 550 mg, 2.5 mmol), and DIEA (1.15 ml, 6.6 mmol) in n-butanol (5 ml). The resulting suspension was set to microwave heating (CEM Discover System) at 150° C. for 3 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 25-35% EtOAc (20% v/v MeOH) in hexanes to give 267 mg (35% isolated yield) of the title compound. 1H NMR: 11.99 (s, 1H) 9.91 (s, 1H) 9.42 (s, 1H) 7.88 (d, J=6.03 Hz, 1H) 7.59 (d, J=10.55 Hz, 1H) 6.95-7.20 (m, 3H) 5.99 (s, 1H) 5.02-5.21 (m, 1H) 1.89-2.03 (m, 1H) 1.76-1.89 (m, 1H) 1.45 (d, J=7.54 Hz, 3H) 0.87 (t, J=8.67 Hz, 2H) 0.75 (d, J=6.03 Hz, 4H) 0.54-0.66 (m, 2H). MS: Calcd.: 463. Found: [M+H]+ 464.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:26][CH2:27][CH2:28][CH3:29])=O.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:26]([C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:9][OH:8])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of lithium aluminium hydride (1.2 g) in dry tetrahydrofuran (100 mL) add 4-butyl-2-(4-trifluormethyl-phenyl)-thiazol-5-carboxylic acid methyl ester (5.3 g, 15.4 mmol) dissolved in tetrahydrofuran (100 mL). Stir the reaction mixture at room temperature over a period of one hour. Add a saturated aqueous solution of ammonium chloride (50 mL) and then a 1 molar aqueous solution of hydrochloric acid (50 mL). Extract the reaction mixture five times with portions of 60 ml of ethyl acetate. Dry the combined extracts with MgSO4 and remove the solvent under reduced pressure to provide [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol (4.6 g) as a yellow oil, which solidified upon standing at room temperature.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=1)[C:7]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:6]=1[S:5]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=1)[C:7]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:6]=1[S:5]2)(=[O:26])[CH3:25]
Reactant: COc1ccc2c(c1)sc1nc(N)nc(=Nc3ccccc3)n12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc2c(c1)sc1nc(NC(C)=O)nc(=Nc3ccccc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2-Amino-8-methoxy-4-phenylimino-4H-1,3,5-triazino[2,1-b]benzothiazole (0.3 g) and acetic anhydride (0.14 g) in dry pyridine (15 mls) were heated at 100° for 24 hours. After cooling to room temperature, methanol (5 mls) was added, the solution was stirred for 1 hour and the solvents were removed in vacuo. The residue was dissolved in chloroform, the solution washed with water, brine, dried (Na2SO4) and evaporated in vacuo to give a yellow solid (0.27 g). Purification by chromatography (silica gel, chloroform) gave the title compound as pale yellow crystals (0.18 g), mp 248°-29°.
Reaction SMILES: [CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([NH:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7]2)=[CH:9][CH:10]=1)#[CH:15]
Reactant: CCCNC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(NCCC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; propyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine (Intermediate 119, 80.0 mg, 0.30 mmols) in methanol (8 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight at ambient temperature. The crude alkyne (58 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO.CCOC(C)=O.CO.[Pd]>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CNC(=O)CC(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Reaction time: 48 h

Procedure:
To a solution of N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXVIII (990 mg, 3.41 mmol) in EtOH/EtOAc/MeOH (5/2/1, 40 ml) was added Pd/C (5%, 90 mg). The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for 48 hours. Degoussa-type catalyst (10% Pd/C, catalytic amount) was added to the mixture. The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for additional 6 hours. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH, hot EtOH and DCM. The filtrate was concentrated affording N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-propionamide LXIX as a light orange foamy solid in quantitative yield (1.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22]O)[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].NC1C=CC(Br)=C2C=1[C:32](=[O:34])N(C)C2.CC1(C)C(C)(C)OB(C2C=NN(CCCCO)C=2)O1>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:32][OH:34])[CH:19]=2)=[C:11]2[C:3]=1[C:4](=[O:5])[N:6]([CH3:7])[CH2:9]2
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Product: CN1Cc2c(-c3cnn(CCCCO)c3)ccc(N)c2C1=O
Yield: 22 %

Procedure:
Prepared analogously to Compound 3C using 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 17D, 300 mg, 1.24 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 364 mg, 1.37 mmol) to afford 81 mg of the title compound (22%). 1H NMR (400 MHz, CDCl3) d 7.65 (s, 1H), 7.50 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 5.25 (br. s., 2H), 4.38 (s, 2H), 4.23 (t, J=7.0 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 3.18 (s, 3H), 1.98-2.08 (m, 2H), 1.60-1.66 (m, 2H) [OH obscured].