Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)O)C2
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.5 g (63%) of (S)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 74°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC1CCCCC1C(=O)O
Product: CC1CCCCC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use 2-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield). 1H NMR (300 MHz, CDCl3) δ 8.08, 8.00, 7.00, 3.50-4.00, 2.70, 2.05, 1.20-1.90, 0.90, 0.75, 0.45, 0.10. MS (ES+) m/z 400 (M+1,).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=1.N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:14](=[O:15])[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)([CH3:21])[C:17]([F:19])([F:20])[F:18])[CH:23]=1
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(OCc1ccc2ccccc2c1)(C(=O)OCc1cccnc1)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (4.3 g.) in benzene (20 ml.) is added, dropwise below 10° C., to a stirred solution of 3-pyridylmethanol (1.20 g.) and pyridine (1.10 g.) in benzene (20 ml.) and light petroleum (5 ml. b.p. 40°-60° C.). The mixture is stirred at 5° C. for 1 hour, and at ambient temperature for 18 hours. The mixture is filtered. The filtrate is diluted with ether, washed with water, aqueous sodium carbonate and water, dried with sodium sulphate, and evaporated to give an oil (4.1 g.). The oil is dissolved in a mixture of ethyl acetate, ethanol, and triethylamine (200:1:1) and is chromatographed on a column of silica gel (210 g.) made up in the same solvent. The column is eluted portionwise with the solvent. The first 350 ml. elutes an impurity (0.1 g.). The following 420 ml. of eluant is evaporated to give (±)-3-pyridylmethyl-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (3.9 g.) as a syrup.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:8][NH:7][N:6]=1)=[O:4]>[OH-].[Na+].CO>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][NH:7][CH:8]=2)=[O:19])=[CH:17][CH:16]=1
Reactant: COC(=O)c1n[nH]cc1NC(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2c[nH]nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
A mixture of 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester (486 mg) in 2 M aqueous NaOH/MeOH (1:1, 50 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, water (100 ml) added and the mixture taken to pH 5 using 2M aqueous HCl. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid as a gray solid (345 mg). (LC/MS: Rt 2.35, [M+H]+ 246.09).
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([CH2:23][CH3:24])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1.CO>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][OH:21])=[CH:17][CH:18]=3)[CH:9]=[C:8]([CH2:23][CH3:24])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(Cc2ccc(CC(=O)O)cc2)nc(C2CCCC2)n1
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(Cc2ccc(CCO)cc2)nc(C2CCCC2)n1
Yield: 27.9 %

Procedure:
A solution of 2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid (0.050 g, 0.15 mmol) in THF (5 mL) at rt under a nitrogen atmosphere was treated with BH3.SMe2 (0.047 g, 0.62 mmol) and the mixture was heated at 55° C. for 4 h. After this time, the mixture was cooled, diluted with methanol, and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.013 g, 30%) as a yellow oil. MW=310.43. 1H NMR (DMSO-d6, 500 MHz) δ 7.22-7.17 (m, 2H), 7.16-7.11 (m, 2H), 7.00 (s, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.93 (s, 2H), 3.60-3.53 (m, 2H), 3.21 (quin, J=8.1 Hz, 1H), 2.71-2.58 (m, 4H), 2.01-1.91 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.69 (m, 2H), 1.67-1.57 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); APCI MS m/z 311 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([NH:9][CH:10]=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])=[N+:22]=[N-:23]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([N:9]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:21]=[N+:22]=[N-:23])[CH:10]=[O:11])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC=O)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N(C=O)C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A stirred solution of (2S)-2-formylamino-propionic acid tert-butyl ester (3.524 g, 20.3 mmol) in anhydrous THF (50 mL) was treated at −78° C. with LDA (20.3 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (20.6 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated and residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the sub-title compound as a pale yellow oil (3.437 g, 53%): 1H NMR (400 MHz CDCl3) δ 1.49 (9H, s), 1.60 (3H, d) 5.18 (1H, m), 7.27 (2H, m), 7.40 (1H, d), 7.59 (1H, t), 8.60 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[CH:6]=1.[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:29]2[C@H:28]([CH3:27])[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(2-bromomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16]C)=[N:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.N1C=CC=CC=1>ClCCl.O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Temperature: 200 °C

Procedure:
A mixture of 5-(3,5-dichloro-pyridin-2-yloxy)-2-methoxy-pyridine (2.39 g, 8.82 mmol) and pyridine hydrochloride (7.00 g, 60.6 mmol) was heated in a kugelrohr apparatus at 200° C. for 25 minutes. After cooling to room temperature dichloromethane and water were added. The solid material, which was insoluble in dichloromethane and water, was isolated by suction and dried in a vacuum oven at 45° C., yielding the title compound, which was used without further purification.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CC1.Br[CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14](=[O:22])[CH2:13]1.C(N(CC)CC)C>O1CCCC1>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([CH:12]=[CH:13][C:14]2=[O:22])=[CH:19][CH:18]=1
Reactant: O=C1CC(Br)c2ccc(Cl)cc21
Agent: O=C1CCc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=Cc2ccc(Cl)cc21

Procedure:
Further exemplary methods of synthesis include conversion of indanone A to intermediate C via treatment of 3-bromo-6-chloro-indan-1-one (A; for references on this material, see: Bøgesø EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361; each herein incorporated by reference in its entirety) with a base such as triethylamine in a solvent such as tetrahydrofuran at ambient temperature (Scheme 1). Removal of the precipitated amine hydrobromide salt by filtration and concentration of the filtrate will afford 6-chloro-inden-1-one (B). This material can be reacted with phenyl-d5-boronic acid in the presence of approximately 1 equivalent of a base such as triethylamine and a catalytic amount of a 1:1 mixture of [Rh(ndb)2]BF4 (bis(norbornadiene)rhodium(I) tetrafluoroborate) and racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in a suitable solvent (e.g. approximately 10:1 solvent mixture of 1,4-dioxane and water) under an atmosphere of argon at elevated temperature (e.g. about 100° C.). Work-up will afford racemic 6-chloro-3-phenyl-d5-indan-1-one (C).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[N:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34](I)=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=3)=[O:29])=[CH:23][CH:22]=2)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:34]2[C:33]([C:38]([F:39])([F:40])[F:41])=[CH:32][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([N:14]4[C:15]5=[N:16][CH:17]=[CH:18][CH:19]=[C:20]5[N:12]=[CH:13]4)=[CH:26][CH:25]=3)=[CH:36][CH:35]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(I)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-cyanophenylboronic acid (62 mg, 0.42 mmol, 2 equiv) in EtOH (0.2 mL) is added dropwise to a mixture of 2-(4-imidazo[4,5-b]pyridin-3-yl-phenyl)-N-(4-iodo-3-trifluoromethyl-phenyl)-acetamide (Example 12) (110 mg, 0.21 mmol), PdCl2(dppf)2 (5 mg, 0.01 mmol, 0.03 equiv), Na2CO3 (2 M solution in H2O, 0.42 mL, 0.84 mmol, 4 equiv) in toluene (1 mL) at reflux. The reaction mixture is stirred at reflux for 1 h, allowed to cool to rt and diluted with EtOAc and H2O. The aqueous layer is separated and extracted twice with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Silica gel column chromatography purification (CH2Cl2/MeOH, 96:4) provides the title compound as a white solid: ES-MS: 495.9 [M-H]−; single peak at tR=4.68 min (System 1); Rf=0.15 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]1([N:21]([CH3:32])[S:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C(=O)C.O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:7])([CH3:8])[C:4]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:32])(=[O:24])=[O:23])=[CH:26][CH:27]=1)=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a cooled (-20° C.) solution of α-trifluoromethyl lactic acid 0.20 g in dry N,N-dimethylacetamide (4 ml) was added thionyl chloride (0.16 g). The reaction mixture was stirred for 1 hour, then warmed to 0° C. over 30 minutes and treated with 4-(N-phenyl-N-methylaminosulfonyl)aniline (0.34 g). After stirring at 22° C. for 24 hours, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4) and concentrated at reduced pressure to give an oil which was purified by chromatography (1:1 hexane: ethyl aceate) and recrystallised from methyl-t-butyl ether/hexane to produce the title compound as a colourless solid (0.31 g); mp 147°-149° C.; MS: m/z=403(M+1); NMR (250 MHz): 1.55 (s,3), 3.09 (s,3), 7.05-7.08 (m, 2), 7.28-7.43 (m,5), 7.53 (s,1), 7.91-7.95 (m,2), 10.36 (broad s, 1). Analysis for C17H17F3N2O4S: Calculated: C, 50.78; H, 4.26; N, 6.97; Found: C, 50.80; H, 4.37; N, 6.93.
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].C(N(CC)CC)C.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[NH:25][C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[N:25]([C:17]1[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:16]=1)[C:26]([O:28][CH3:29])=[O:27])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)N(C(=O)OC)c1nc2ccccc2[nH]1
Reaction time: 12 h

Procedure:
4.1 parts of triethylchlorosilane and 3.0 parts of triethylamine are separately added, in portions, to 5 parts of methyl benzimidazole-2-carbamate in 50 parts of tetrahydrofuran. After 12 hours, the mixture is filtered and the solvent is distilled from the filtrate under reduced pressure. 1.6 parts of methyl N-triethylsilyl-benzimidazole-2-carbamate are obtained; decomposition point >120° C. (active ingredient No. 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][N:27]([CH2:38][CH:39]([CH3:41])[CH3:40])[S:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([O:37][C:34]2[CH:35]=[CH:36][C:31]([S:28](=[O:29])(=[O:30])[N:27]([CH2:26][C:25]3[CH:42]=[CH:43][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:32][CH:33]=2)[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To a solution of 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (354 mg, 1.8 mmol) in EtOH (5 mL) was added K2CO3 (246 mg, 1.8 mmol) and a solution of N-(4-chloro-benzyl)-4-hydroxy-N-isobutyl-benzenesulfonamide (629 mg, 1.78 mmol) in EtOH (5 mL) and the reaction was heated at 95° C. for 16 hours. The reaction was left to cool to room temperature and concentrated. Water and EtOAc were added, extracted, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give (+/−)trans-4-{4-[(4-chloro-benzyl)-isobutyl-sulfamoyl]-phenoxy}-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (259 mg, 26%). LCMS (m/z, Method A) ES+ 553 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[C:5]=2[C:4](=[O:30])[CH2:3]1.[OH-:32].[Na+].OO>C(O)C.CS(C)=O.O>[CH3:1][C:2]1([CH3:31])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:32])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([C:26]([F:28])([F:29])[F:27])[C:5]=2[C:4](=[O:30])[CH2:3]1
Reactant: [OH-]
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C(N)=O)c(NC4CCOCC4)c3)c2C1
Yield: 98 %

Procedure:
To a solution/suspension of 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (772 mg, 1.79 mmol, 1.0 eq) in 10 mL of 4:1 ethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes the reaction mixture was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (788 mg, 98%) as a tan solid: LC/MS (m/z): [M+H]+ 451.2.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](=[O:27])(=[O:26])[NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:27])=[O:26])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-methyl-4-(6-(N-(pyrimidin-4-yl)sulfamoyl)isoquinolin-1-yl)piperazine-1-carboxylate (0.043 g, 0.089 mmol) was dissolved in DCM (0.887 ml) and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for one hour at room temperature. The reaction was concentrated, triturated with ether, and filtered. The solids were washed with ether and vacuum dried to afford 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate as a yellow solid. (ESI) 385.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B(O)O)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 39.6 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,4-dimethoxypyrimidin-5-boronic acid (176 mg, 0.96 mmol) were reacted. After purification the title compound (73 mg, 39% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6 ) δ 9.04 (d, J=4.9 Hz, 1H), 8.57 (dd, J=5.6, 9.3 Hz, 1H), 8.37 (s, 1H) 7.77 (t, J=9.1 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 3H), 2.93 (m, 1H), 0.70(m, 4H). MS APCI, m/z=385.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([O:16][CH2:17][CH2:18][OH:19])=[N:10][C:11]([F:15])=[C:12]([Cl:14])[CH:13]=1.[Cl:20][C:21]([Cl:26])([CH3:25])[C:22](Cl)=[O:23]>C(#N)C>[Cl:20][C:21]([Cl:26])([CH3:25])[C:22]([O:19][CH2:18][CH2:17][O:16][C:9]1[C:8]([Cl:7])=[CH:13][C:12]([Cl:14])=[C:11]([F:15])[N:10]=1)=[O:23]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: OCCOc1nc(F)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Cl)(Cl)C(=O)OCCOc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution was prepared by admixing 250 milliliters of acetonitrile, 55.3 grams (0.4 mole) of potassium carbonate, 42.5 grams (0.16 mole) of 2-(3,5-dichloro-6-fluoro-2-pyridyloxy)ethanol and 32.3 grams (0.2 mole) of 2,2-dichloropropionyl chloride. This mixture was stirred at room temperature for 4 days. The solids which formed were removed by filtration and the filtrate was concentrated under a reduced pressure. The residual material which remained was dissolved in hexane and washed with water. The hexane was removed under a reduced pressure to yield a pale-orange liquid having a refractive index of n/25D=1.5239. The product was confirmed to be 2-(3,5-dichloro-6-fluoro-2-pyridyloxy)ethyl 2,2-dichloro propionate by its infrared and nuclear magnetic resonance spectrums.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH:12]=[CH2:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]#[CH:22])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:11]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)[C:3]=2[CH:10]=[CH:9]1)[CH:12]=[CH2:13]
Reactant: C#Cc1cccc(N)c1
Reactant: C=CCn1ccc2c(Cl)ncnc21
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CC=C)c1
Temperature: 125 °C
Yield: 40.7 %

Procedure:
To 4-chloro-7-allyl-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.6 mmol) in dry MeOH (5 ml) was added m-aminophenyl acetylene (0.36 g, 3.1 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 20 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (50 g, 40 mm mesh) using 3% MeOH/CH2Cl2 to afford the title compound as a yellow powder (0.29 g, 41%): TS-MS: 275 (MH+); anal. RP18-HPLC RT: 4.62 minutes.