Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1.C=O.[C:43](O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:43])[CH2:38][CH2:39]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CCC4CCNCC4)c3)ccc21
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CCC(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide (1 eq) in methanol was added formalin (2 eq) and acetic acid (5%) followed by sodium cyanoborohydride (2 eq) and the resulting mixture was stirred at ambient temperature for 3 h. LC MS showed formation of the product. The crude mixture was then concentrated and to it was added sodium bicarbonate and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and purified by preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methylpiperidin-4-yl)propanamide.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41](O)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1.CCOC(C)=O>[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:24])[N:7]=2)[N:18]=4)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(O)cc2OCC3)n(C(C)C)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.92 mmol), 4-(1-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (308 mg, 1.11 mmol) and triphenylphosphine (411 mg, 1.38 mmol) in dioxane (5 mL) was added dropwise DEAD (217 ul, 1.38 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was then diluted with EtOAc and washed with NaOH aq. (1N). The organic phase was washed with brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording 4-{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]propyl}piperidine-1-carboxylic acid benzylester (280 mg, 51%). 1H NMR (CDCl3, 400 MHz): δ 8.40 (1H, d, J=8.97 Hz), 7.59 (1H, s), 7.37-7.28 (5H, m), 6.73 (1H, dd, J=8.99, 2.56 Hz), 6.54 (1H, d, J=2.52 Hz), 5.98-5.87 (1H, m), 5.14 (2H, s), 4.51-4.45 (2H, m), 4.44-4.37 (2H, m), 4.34-4.19 (2H, bs), 4.09-4.03 (1H, m), 2.83-2.68 (2H, m), 2.43 (3H, s), 1.88-1.78 (1H, m), 1.75-1.61 (5H, m), 1.58 (6H, d, J=6.65 Hz), 1.38-1.30 (1H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Yield: 50.2 %

Procedure:
{(S)-1-[1-(3-Cyanocyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.21 g, 0.586 mmol) was added to 20% TFA in DCM (7 mL) and the resultant solution stirred at 20° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH, then the product was eluted with 2M NH3/MeOH and concentrated in vacuo to give title compound as a colourless solid (0.076 g, 51%). LCMS (Method J): RT 1.52 min [M+H]+ 259
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([C:19]1[N:24]=[C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][CH:20]=1)[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C1OCCOC1>[CH3:28][C:27]([CH3:29])([CH3:30])[C:26]([NH:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:17]([O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:18])[N:24]=1)=[O:31]
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: CC(Br)c1cccc(NC(=O)C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Product: CC(ON=C(c1ccccc1)c1nnnn1C)c1cccc(NC(=O)C(C)(C)C)n1
Reaction time: 36 h
Yield: 98.2 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (10 g, 49.21 mmol, 1 eq.) in 250 ml of dioxanne, was added N-[6-(1-bromoethyl)pyridin-2-yl]-2,2-dimethylpropanamide (14 g, 49.21 mmol, 1 eq.), then was added cesium carbonate (16 g, 49.21 mmol, 1 eq.), and then was added potassium iodide (0.81 g, 4.92 mmol, 0.1 eq.). The reaction mixture was stirred for further 36 hrs. After evaporation of the solvent, the white residue was taken up with 200 ml of water, triturated and filtered, yielding to 2,2-dimethyl-N-{6-[1-({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)ethyl]pyridin-2-yl}propanamide (19.7 g, 90% pure, 88% yield) after air-drying.
Reaction SMILES: CO[C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:28][NH2:29].C(OCC)(=O)C.O>C(O)C>[NH:28]([C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:29]
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1c(CC(N)=O)c2c(OCC(=O)NN)cccc2n1Cc1ccccc1
Yield: 91 %

Procedure:
A mixture of 484 mg (1.3 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester (Example 39) and 2 mL of hydrazine in 10 mL of ethanol was heated to maintain reflux for 16 hours, 10 mL of ethanol added, heated an additional 4 hours and cooled. Ethyl acetate and water were added and the insoluble material filtered. The ethyl acetate solution was separated, washed with brine, dried (MgSO4) and concentrated. The residue was combined with he precipitate above co give 435 mg (91% yield) of 4-(2-hydrazino-2-oxoethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 207-210° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([C:36](Cl)=[O:37])=[CH:31][CH:30]=[CH:29]3)[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:36]([C:32]2[C:33]3[C:28](=[CH:27][C:26]([O:25][C:21]4[CH:20]=[C:19]([Cl:18])[N:24]=[CH:23][N:22]=4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=2)=[O:37])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(F)cc2)n1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)n(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
560 mg (2.4 mMol) 5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-ylamine and 763 mg (2.4 mMol) 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (see Step 19.3) are dissolved in 5 ml CH2Cl2 and cooled to 0° C. 193 μl (2.4 mMol) Pyridine are added dropwise and after complete addition the reaction is allowed to warm to rt. It is stirred for 2 h at ambient temperature. The reaction is concentrated under reduced pressure and the remaining crude product is purified by flash chromatography (combi-flash, 40 g column; CH2Cl2/MeOH; gradient 0-5% MeOH) to give the title compound as a yellow foam: MS: [M+1]+=517.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[Cl:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>>[Cl:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:28]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)CCl)nc3cc21

Procedure:
3-Chloro-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-chloropivaloyl chloride (115 μl, 0.89 mmol). The title compound was obtained as yellow powder (239 mg, 69%).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li][CH2:9][CH2:10][CH2:11][CH3:12].S(OCCCC)(OCCCC)(=O)=O.[NH4+].[OH-]>CCOCC>[Br:7][C:6]1[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: [Li]CCCC
Agent: CCCCOS(=O)(=O)OCCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCc1cscc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
To a stirred solution of 3,4-dibromothiophene (4.60 g, 20.90 mmol) in dry Et2O (50 mL) at -78° C. was dropwise added n-BuLi (2.5 M, 16.72 mL, 41.80 mmol) under Ar. After stirring for 15 min, a solution of freshly distilled di-n-butyl sulfate in dry Et2O (10 mL) was dropwise added through an addition funnel. The mixture was allowed to warm to room temperature and stirred overnight. 30 mL of 12 M NH4OH was added to the mixture. After stirring for 1 h, the mixture was partitioned between H2O and Et2O. The organic layer was separated and washed with H2O, brine and dried (MgSO4). Removal of the solvent under reduced pressure afforded the title compound as an oil (2.50 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2([OH:21])[CH2:20][N:17]([CH:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Product: OC1(c2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-fluorophenylmagnesium bromide (7.0 mL, 1 .OM (Et2O)) in toluene (20 mL) at −78° C. under argon, was added, dropwise, a solution of 1-diphenylmethyl-3-azetidinone (3) (1.4 g) in toluene (30 mL) over 30 minutes. The mixture was stirred for 4 hours at −78° C. then warmed to room temperature and partitioned between aqueous ammonium chloride solution (50 mL) and diethyl ether (3×20 mL). The combined organic fractions were washed (water, brine), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate, hexane) gave 3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (1.82 g). To a stirred solution of the free base (1.82 g) in ether (5 mL) was added dropwise a solution of oxalic acid (0.49 g) in acetone (1 mL). The mixture was stirred for 5 minutes then filtered to give the oxalate salt hemihydrate (2.23 g), m.p. 75° C. (acetone). Found: C, 66.71; H. 5.34; N, 3.04. C24H22FNOs.0.5H2O requires C, 66.67; H, 5.32; N, 3.17%.
Reaction SMILES: [OH:1][CH:2]1[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[C:7]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@H:22]4[C:27]5[CH:28]=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[CH:31][C:26]=5[CH2:25][CH2:24][O:23]4)[C@H:16]([CH3:35])[CH2:15]2)=[CH:6][CH:5]=[C:4]3[CH2:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:35][C@@H:16]1[CH2:15][N:14]([C:7]2[C:8]3[C:13]4[C:4]([CH2:3][C:2](=[O:1])[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:5][CH:6]=2)[CH2:19][CH2:18][N:17]1[CH2:20][CH2:21][C@H:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[CH:31][C:26]=2[CH2:25][CH2:24][O:23]1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)C(O)C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)C(=O)C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S)-1-{2-[(2R)-4-(1-hydroxy-1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide (0.10 g, 0.21 mmol) in dry DMF (2 mL), cooled to 0° C. under nitrogen, was added pyridinium dichromate (0.08 g, 0.21 mmol), and the mixture stirred for 4 h, allowing the reaction to warm to room temperature. A further equivalent of pyridinium dichromate was added and the reaction stirred for a further 1 h. The mixture was poured onto water and the resultant precipitate filtered off. Purification by preparative LC-MS yielded (1S)-1-{2-[(2R)-2-methyl-4-(1-oxo-1,2-dihydro-5-acenaphthylenyl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide. M+H=470.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>[Pd].CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(-c2[nH]cc(C3=CCNCC3)c2-c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(-c2[nH]cc(C3CCNCC3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
120 mg of 10% palladium on carbon were added to a solution of 120 mg (0.306 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrole dihydrochloride [prepared as described in Example 10 above] in 10 ml of methanol. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour, after which the reaction mixture was filtered. The filtrate thus obtained was concentrated by evaporation under reduced pressure. Water was added to the resulting residue and then this mixture was made alkaline with a 1 N aqueous solution of sodium hydroxide. The resulting precipitate was collected by filtration to give 84 mg (yield 85%) of the title compound as a pale red powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:44]=[CH:43][C:6]2[CH:7]([C:17]3[C:18](=[O:42])[NH:19][C:20](=[O:41])[N:21]([C:23]4[N:28]=[C:27]([NH:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:26]([N+:38]([O-:40])=[O:39])=[CH:25][N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:44]=[CH:43][C:6]2[CH:7]([C:17]3[C:18](=[O:42])[NH:19][C:20](=[O:41])[N:21]([C:23]4[N:28]=[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]([N+:38]([O-:40])=[O:39])=[CH:25][N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ncc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)n2)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ncc([N+](=O)[O-])c(NCC(=O)O)n2)c(=O)[nH]c1=O

Procedure:
A solution of the product from example 28 step (ii) (0.07 g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stirred overnight and evaporated. The residue was triturated with ether and filtered off. Yield 0.05 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)NCCN5CCCC5)cc4)nnc3c2)c1
Yield: 95.4 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.157 g, 0.523 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.261 g, 0.785 mmol, 1.5 equiv), cesium carbonate (0.512 g, 1.57 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.061 g, 0.10 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.048 g, 0.052 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (5 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot, and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation provided slightly impure product. Solids were diluted in minimum amount of DCM and precipitated out using excess hexanes. The resulting solids were filtered off and dried to yield a yellow powder (0.276 g, 95% yield). MS (ESI+): m/z=553.3, LC retention time: 2.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:37])[C:5]([NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][CH:11]([S:13][C:14](=O)C)[CH3:12])=[O:8].CI.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:17]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH:11]([S:13][CH3:14])[CH3:12])[C:5]([NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)=[O:20])=[C:4]([CH3:37])[CH:3]=1
Reactant: CC(=O)SC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Solvent: CO
Product: CSC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 2.3 g (4.0 mmol) thioacetic acid S-[2-(5-chloro-2-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-3-methyl-benzoylamino)-1-methyl-ethyl]ester in 100 ml MeOH is added 1 ml MeI at a temperature of 5° C., followed by a solution of 0.8 g NaOH in 15 ml H2O. After 30 minutes, the clear solution is evaporated. The residue is triturated with 300 ml water (pH brought to 5 by adding HCl 1N). The crystals are filtered and washed with water and hexane (2.0 g, 92%, m.p.: 140-145° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:5][CH:4]=1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:19]([OH:24])(=[O:25])[CH2:20][CH2:21][C:22]([OH:2])=[O:23].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)O1
Agent: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)O
Temperature: 135 °C

Procedure:
A mixture of 4-methoxybenzoin (20 g, 0.083 mole) and succinic anhydride (9.1 g, 0.091 mole) in toluene (6 mL) is heated for 7 hours under nitrogen at 135° C. (internal temp.). The solution is poured into 0.SN-NaHCO3, the organic layer was separated and reextracted with 0.5SN-NaHCO3. The combined extracts are washed with ether and then acidified in the cold with concentrated HCl. The liberated oil is extracted with ethyl acetate (3x), the extracts washed with water and dried (MgSO4). Removal of the solvent yields a yellow solid (20.89 g, 73.8%), m.p. 104°-108° C. It is used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M114) (0.50 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (274 mg, 68%).