Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]2[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]3[CH:8]=[C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])[CH:12]=[CH:11][N:10]3[N:13]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.19 g, 0.44 mmol), 3-boronobenzoic acid (0.11 g, 0.67 mmol), cesium carbonate (0.22 g, 0.67 mmol), dioxane (3.7 mL) and water (0.74 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.0090 g, 0.010 mmol). The solution was maintained at 95° C. for 7 h. The solution was cooled to room temperature, concentrated and dissolved in a solution containing water and methanol (1.8/1, 14 mL). The solution was filtered to remove fine particulates and washed with dichloromethane (3×5 mL). The aqueous portion was concentrated to dryness to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid as a pale grey solid which was used without further purification. LCMS: retention time: 1.830 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 390 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH3:13]C1C=CC(S(C)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(O)C>[CH3:11][C:6]1[CH:5]=[C:4]([O:12][CH3:13])[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-dimethyl-4-nitrophenol (33.43 g), methyl p-toluene sulfonate (40.97 g) and K2CO3 (31.79 g) are stirred at reflux in 200 ml of acetone for four and one half hours and then stirred at R.T. overnight. The reaction mixture is filtered to give a dark amber filtrate. The filtrate is concentrated in vacuo to a yellowish brown solid which is dissolved in ethyl acetate washed with saturated aqueous sodium chloride, dried and concentrated in vacuo. The concentrate is distilled (87°-104° C./0.10 mm) to give a yellow waxy looking solid. The solid is dissolved in hot ethanol and recrystallized, M.P. 50°-52° C.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH2:24][CH3:25])[C:22]([CH2:26][CH3:27])=[N:21][C:20]=2[CH3:28])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>S(Cl)(Cl)=O.C(O)(C)C>[CH2:24]([N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:9][CH:8]=3)[N:18]=2)=[C:20]([CH3:28])[N:21]=[C:22]1[CH2:26][CH3:27])[CH3:25]
Reactant: COCCN
Reactant: O=S(=O)(O)Cl
Reactant: CCc1nc(C)c(-c2ccnc(Nc3ccccc3)n2)n1CC
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CCc1nc(C)c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1CC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1,2-diethylmethylimidazol-5-yl)pyrimidine (Method 13; 28 mg, 0.09 mmol) in thionyl chloride (2 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of 2-methoxyethylamine (300 μl, 3.45 mmol) in isopropanol (2 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Water (20 ml) was added and extracted EtOAc (2×20ml). The organic layers were combined, dried and evaporated in vacuo to give the title compound (16 mg, 40%) as a orange solid. NMR 2.35-2.45 (m, 9H), 2.7 (q, 2H), 2.89 (q, 2H), 3.40-3.28 (m, 2H), 3.60-3.58 (m, 3H), 4.35 (m, 2H), 7.0 (d, 1H), 7.49 (t, 1H), 7.70 (d, 2H), 7.9 (d, 2H), 8.55 (d, 1H); m/z 445.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#N.[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:1]=[CH:3][C:4]3[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=2)[S:10][N:9]=1
Reactant: N#CCC(N)=O
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Product: N#Cc1c(O)nsc1Nc1ccc(C=Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 1-isothiacyanato-4-styryl-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (300 MHz, DMSO-d6) δ: 7.22–7.65 (m, 11H). MS (ES, m/z): 320.3, [M-H]+, 318.1 [M-H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH2:20])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[CH2:27]([CH:34]([CH2:39][Br:40])[CH2:35][C:36](Cl)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CO>ClCCl.[Cl-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH:20][C:36](=[O:37])[CH2:35][CH:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:39][Br:40])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CC(CBr)Cc1ccccc1
Reactant: NN=C(Cc1ccnc2ccccc12)c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CC(CBr)Cc1ccccc1)NN=C(Cc1ccnc2ccccc12)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine (2.25 g, 8.40 mmol) in anhydrous dichloromethane (100 mL) and pyridine (1.81 mL, 22.4 mmol) is cooled to −78° C., treated with a solution of 3-benzyl-4-bromo-butyryl chloride (2.1 g, 7.8 mmol) in dichloromethane (10 mL), and stirred for 2 h. The mixture is treated with methanol (3 mL), stirred for 10 min, and diluted with saturated ammonium chloride solution (30 mL). The mixture is diluted with dichloromethane (300 mL), washed with water (2×50 mL) and brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is precipitated from ether to yield the title compound, 2.3 g (60%), as a pale yellowish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[O:27]([CH2:34][CH2:35][NH2:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:36][CH2:35][CH2:34][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NCCOc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=S(=O)(Nc1cccc2nc(NCCOc3ccccc3)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=456.4 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 3,5-difluorophenyl-sulfonylchloride and 2-phenoxyethylamine.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC(OC)=C(C[OH:31])C=1)(C)(C)C.C(Br)(Br)(Br)Br.CCCCCCC>C(Cl)Cl>[C:14]1([P:7](=[O:31])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(C)(C)C)cc1CO
Agent: BrC(Br)(Br)Br
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
Triphenyl phosphine (5.84 g, 22.3 mmol) was added to a solution of (5-tert-butyl-2-methoxyphenyl)methanol (4.20 g, 21.8 mmol) in anhydrous DCM (80 ml) and the mixture cooled to 10° C. Carbon tetrabromide (7.39 g, 22.3 mmol) was added with stirring over 10 min, and after 30 min the temperature was raised to ambient temperature. Stirring continued for 17.5 h when the solvent was lowered to 20 ml under reduced pressure. Addition of heptane (80 ml) with stirring resulted in precipitation of triphenyl phosphine oxide, which was removed by filtration of the mixture through dicalite. Evaporation of the filtrate gave a straw coloured gum, purification of which was achieved by chromatography on silica using heptane:DCM (1:1) as eluent to afford 2-bromomethyl-4-tert-butyl-1-methoxybenzene as a clear gum (2.02 g, 36%).
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][O:27]C(=O)C)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO.C[O-].[Mg+2].C[O-]>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][OH:27])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)OC(=O)c1ccccc1
Reaction time: 3 h
Yield: 67 %

Procedure:
(R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (8.5 g, 19.73 mmol) in a mixture of chloroform (80.0 ml, 992 mmol) and methanol (60.0 ml, 1483 mmol) was added magnesium methoxide (4.18 ml, 39.5 mmol). After 3 h, quenched with 1.0 M HCl and extracted with dichloromethane (300 mL). The crude product was purified by flash chromatography using 70% EtOAc in hexane to give (R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate in 67% yield. 1H NMR (500 MHz, CDCl3): in δ 8.09 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.47 (m, 1H), 7.32 (t, J=8 Hz, 2H), 7.22 (s, 1H), 5.49 (m, 1H), 4.99 (m, 2H), 3.45-3.41 (m, 1H), 3.68 (s, 3H), 3.36-3.31 (m, 1H); MS (ESI) 389 (M+H); Rf=2.07.
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=O)=[N:26][CH:27]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@@H:8]([NH:7][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:27][N:26]=1)=[O:30])[CH2:9]2
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)cn1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 5-(trifluoromethyl)picolinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.98 (s, 1H), 8.22 (dd, J=8 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 6.36 (s, 1H), 4.11 (m, 1H), 3.39 (dd, J=16 Hz, 1H), 2.83-2.77 (m, 4H), 2.56 (ddd, J=16 Hz, 1H), 2.00 (m, 1H), 1.66 (m, 3H), 1.50 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]([SH:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:16]1([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:22])[C:2]([S:34][C:31]3[NH:30][C:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)=[N:33][N:32]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1
Temperature: 55 °C
Yield: 27 %

Procedure:
A solution of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (150 mg, 0.46 mmol, from Step 1 below), 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (82 mg, 0.46 mmol), and triethylamine (64 □L, 0.46 mmol) dissolved in DMF (5 mL) was heated to 55° C. under N2 for 8 h. The resulting mixture was concentrated and purified by Prep HPLC to give the title compound (58 mg, 27%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CO.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([I:12])=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: CC#N
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 60 °C
Yield: 55.7 %

Procedure:
4-Chloro-6-methylpyrimidin-2-ylamine (5 g, 0.04 mol) was suspended in acetonitrile (50 mL) and methanol (50 mL) and N-iodosuccinimide (12 g, 0.05 mol, 1.5 equiv.) added to the resulting mixture. The mixture was heated to 60° C. under a nitrogen atmosphere for 3 h. A solid precipitated in the resulting brown mixture and was isolated by filtration and washed with cyclohexane to give a white crystalline solid 6 g, 65%. Additional product (˜2.5 g) was present in the mother liquors. LCMS m/e 270 35Cl/272 37Cl (M++1);
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH2:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:29].[H-].[Na+].[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44].O>CN(C=O)C>[CH3:41][N:42]([CH3:46])[C:43]([N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:28](=[O:29])[CH2:27][CH2:26][C:3]2[N:4]=[CH:5][N:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])=[CH:31]1)=[O:44]
Reactant: Cc1c(CCC(=O)c2c[nH]c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)c2cn(C(=O)N(C)C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(1H-indol-3-yl)-1-propanone (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 40 mg) in dry DMF (1 ml) under nitrogen. After 15 min. dimethylcarbamyl chloride (0.11 ml) was added and the mixture was stirred for 20 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (815 mg) which was purified by FCC (column made up in ethyl acetate:triethylamine 99:1) eluting with ethyl acetate to give the title compound (445 mg) as a foam, t.l.c. on triethylamine impregnated silica (ethyl acetate) Rf 0.20.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:26][C@H:14]2[O:15][C:16]3[CH:21]=[C:20]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:25])=[CH:18][C:17]=3[C@@H:13]2[CH2:12][CH2:11]1>>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:26][C@H:14]2[O:15][C:16]3[CH:21]=[C:20]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:25])=[CH:18][C:17]=3[C@@H:13]2[CH2:12][CH2:11]1
Reactant: Cl[Mg]c1ccccc1
Reactant: C=CCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@H]1O2
Product: C=CCc1cc2c(cc1O)[C@@H]1CCC(O)(c3ccccc3)C[C@H]1O2

Procedure:
The addition of phenyl magnesium chloride to the product of Example 12 can be accomplished following the procedure of Example 9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 25 g, 55.1 mmol) was dissolved in DCM (100 ml, sonication required) and slowly charged with MeOH (100 ml). The solution was cooled in an ice bath then charged with sodium borohydride (2.60 g, 68.8 mmol) portion wise (exothermic) and allowed to stir for 1 h at RT. A large exotherm was observed and the reaction turned dark red. TLC showed product had formed after 20 minutes. The reaction was diluted with 500 mL DCM and 200 mL water. A large amount of dark red to brick red material was filtered off. The aq. layer was extracted with 1×200 mL DCM and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel, 0-10% EtOAc/DCM gave (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 15 g, 32.9 mmol, 59.7% yield) as a pale yellow solid. MS: [M+H]+ m/z 456. 1H NMR (500 MHz, CDCl3) δ 7.34-7.27 (m, 10H), 7.23-7.18 (m, 5H), 5.78 (s, 1H), 4.99 (s, 2H), 3.93 (s, 3H), 3.86 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])=[O:21])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:11]([NH:14][C:15]([NH:1][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)=[O:16])(=[O:13])=[O:12])=[O:21])[CH2:18][CH2:19]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccccc1C(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nc(Cl)cc(Cl)n1)NS(=O)(=O)Nc1ccccc1C(=O)C1CC1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
2-Amino-4,6-dichloropyrimidine (6.15 g, 0.0375 mol) is added portionwise to a solution of chlorosulfonyl isocyanate (5.30 g, 0.0375 mol) in methylene chloride at 0° C. The resulting mixture is stirred at 0° to 2° C. for two hours and a solution of o-aminophenyl cyclopropyl ketone (6.04 g, 0.0375 mol) and triethylamine (3.8 g, 0.0406 mol) in methylene chloride is slowly added to the mixture. The resulting solution is stirred at room temperature overnight, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (14.3 g, 75% real by HPLC analysis, 68% yield) which is used as a starting material for Example 2 without purification. A portion of the yellow solid is purified to yield the title product, mp 114°-116° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[F:18][C:19]1[C:20]([NH2:33])=[CH:21][C:22]2[CH:23]=[C:24]3[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][N:25]3[C:26]=2[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:20]4[C:19]([F:18])=[CH:27][C:26]5[N:25]6[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]6=[CH:23][C:22]=5[CH:21]=4)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)CCn2c1cc1cc(N)c(F)cc12
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (346 mg, 1.4 mmol), 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (260 mg, 1.2 mmol) and HATU (543 mg, 1.4 mmol) in DMF (5 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)cyclopropanecarboxamide (342 mg, 65%). ESI-MS m/z calc. 442.2, found 443.5 (M+1)+. Retention time 2.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=7.6 Hz, 1H), 7.30-7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.84 (d, J=11.1 Hz, 1H), 6.01 (d, J=0.5 Hz, 1H), 3.98 (t, J=6.8 Hz, 2H), 2.37 (t, J=6.8 Hz, 2H), 1.75 (dd, J=3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J=3.9, 6.9 Hz, 2H) ppm.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O.C(OCC)(=O)C>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: Cc1ccn(C(=O)NC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)n1ccc(CBr)n1
Yield: 32 %

Procedure:
To N-tert-butyl-3-methyl-1H-pyrazole-1-carboxamide (609 mg, 3.36 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (849 mg, 4.77 mmol) and benzoyl peroxide (114 mg, 0.470 mmol). The mixture was heated to reflux overnight and then diluted with water and ethyl acetate. The organic layer was separated, dried and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluting with 10% ethyl acetate in heptane) to give the title compound (280 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4].[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:32])([F:33])[F:34])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 40, 420 mg (0.85 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino] quinoline-2-carboxylic acid methyl ester is dissolved in 10 ml of methanol and mixed with 130 mg (3.41 mmol) of sodium borohydride. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 75 mg (18% of theory) of the product is obtained.