Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43].C(OCC)(=O)C.CCCCCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:42](=[O:44])[CH3:43])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 10 h
Yield: 84.8 %

Procedure:
To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate, 0.24 m; (3 mmoles) of pyridine, 0.5 mg (0.004 mmole) of 4-(dimethylamino)pyridine and 10 ml of dry methylene chloride was added 0.12 ml (1.3 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the solution was stirred at room temperature for 10 hours. The reaction mixture was diluted with 20 ml of methylene chloride and washed with cold 1N-hydrochloric acid. The aqueous layer (washings) was extracted with methylene chloride and the extract was combined with the organic layer. The resulting mixture was washed successively with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 45 mg of 7α-acetoxy- 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate (yield: 85%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[OH:31][CH2:30][CH2:32][NH:33][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Solvent: CS(C)=O
Product: Cn1nnc(-c2cccc(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)n1
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.12 mmol) (from Example 32 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered, washed with methanol and dried to give 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 39.0 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:31][C:12]=2[O:13][C@@H:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:7]=1)=[O:5])[CH3:2].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:31][C:12]=2[O:13][C@@H:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)OC(C)(C)C)c2ccccc2C)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)O)c2ccccc2C)n[nH]1
Yield: 22.8 %

Procedure:
tert-Butyl (R)-4-[2-(5-ethoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (1.7 g) is stirred in trifluoroacetic acid (10 mL) at ambient temperature for 15 minutes. The reaction mixture is basified with saturated sodium bicarbonate solution and a solid is precipitated which is taken up in ethyl acetate (50 mL) and washed with water (50 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. Recrystallisation from ethyl acetate/cyclohexane affords (R)-4-[2-(5-ethoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)-phenoxy]-4-(2-methylphenyl)butanoic acid (0.35 g) in the form of a white solid, m.p. 108-110° C. [Elemental analysis:- C,67.9, H, 5.92, N, 7.64%. Calculated:- C,67.6, H, 5.63, N, 8.16%]
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>C(O)C.C(OCC)(=O)C>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CSc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 95 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97:3 to afford the title compound as a yellow oil that crystallised on standing (2.59 g, 95% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14](OC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)COc1ccccc1
Product: N#Cc1ccnc(-n2nc(COc3ccccc3)cc2O)c1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 3-oxo-4-phenoxybutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O2, 293; Found, 293.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C(\CCCCCOCc1cccnc1)=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.8 g, 3 mmoles) was dissolved in methylene chloride (10 ml), and pyridine (2 ml) and nicotinoyl chloride hydrochloride (0.55 g, 3 mmoles) were added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent to give 1-nicotinyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (1.0 g, 89.6%) (Compound Id-21) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].C([Sn]([CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.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]>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cc1cccnc1)Nc1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (110 mg, 0.27 mmol), 3-(tributylstannanylmethyl)pyridine, Example 90(a), (160 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.027 mmol, Aldrich) and triphenylphosphine (28 mg, 0.11 mmol, Aldrich) in 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100° C. overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3×60 mL). The combined organic extracts were washed with satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-70% EtOAc in hexane) provided the title compound as an orange solid. MP 202-203° C. MS (ESI, neg. ion) m/z: 420 (M−1).
Reaction SMILES: C([O:8][C@H:9]1[C@H:27]([O:28][CH3:29])[C@@H:26]([CH2:30][OH:31])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:10]1[O:32][C@H:33]1[O:62][C@H:61]([CH2:63][O:64]CC2C=CC=CC=2)[C@@H:52]([O:53]CC2C=CC=CC=2)[C@H:43]([O:44]CC2C=CC=CC=2)[C@H:34]1[O:35]CC1C=CC=CC=1)C1C=CC=CC=1.[C@H]1(O[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2OCCCCCCCCC(OC)=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[CH3:29][O:28][C@@H:27]1[C@@H:26]([CH2:30][OH:31])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@H:10]([O:32][C@H:33]2[O:62][C@H:61]([CH2:63][OH:64])[C@@H:52]([OH:53])[C@H:43]([OH:44])[C@H:34]2[OH:35])[C@H:9]1[OH:8]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](OC)[C@H](OCc2ccccc2)[C@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](OC)[C@H](O)[C@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 89.6 %

Procedure:
Compound 41 (52 mg, 0.053 mmol) was hydrogenated as described for the preparation of 44 to provide 61 (25 mg, 89.2%) as a white powder after lyophilization; [α]D +115 (c 0.28, water); 1H-n.m.r. (D2O): δ5.20(d, 1H, J1',2' 3.8 Hz, H-1'), 5.13(d, 1H, J1,2 3.8 Hz, H-1), 3.75, 3.46(s, 3H each, 2×OCH3) 2.39(t, 2H J 7.5 Hz, CH2COO).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[BrH:11]>>[Br:11][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: OC(c1cccs1)C1CC1
Reactant: Br
Product: BrCC/C=C/c1cccs1
Reaction time: 2 h

Procedure:
225 g (1.46 mol) of cyclopropyl-2-thienylcarbinol were added dropwise to 972 ml of 48% strength hydrobromic acid at from 5° to 10° C.in the course of 1 hour. After 2 hours at room temperature, the organic phase was separated off and the aqueous solution was extracted with three times 300 ml of dichloromethane. The combined organic phases were washed neutral with dilute sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down under reduced pressure. 322 g (94% corrected) of crude bromide (GC: 92%) were obtained. 250 MHz-1H-NMR (in CDCl3): δ [ppm]=2.65-2.80 (m, 2H), 3.46 (t, 2H), 5.90-6.10 (m, 1H), 6.61 (d, 1H), 6.80-7.00 (m, 2H), 7.14 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:14]([OH:16])=O)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]([C:14]([Cl:19])=[O:16])=[C:11]=[O:12]
Reactant: Cc1cc(C)c(C(C(=O)O)C(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=C=O)C(=O)Cl)c(Cl)c1
Temperature: 95 °C

Procedure:
7.6 g of 2-chloro-4,6-dimethylphenylmalonic acid according to Example (XXXV-1) were suspended in 22 ml of toluene and treated dropwise with 19.5 ml of thionyl chloride. The mixture was heated at 95° C. for 9.5 h, cooled and freed from the volatile constituents by passing argon through. The residues of thionyl chloride and the solvent were distilled off at 45° C. in a high vacuum. 6.6 g of 2-chloro-4,6-dimethylphenylchlorocarbonylketene were obtained as an oil which was slightly contaminated with 2-chloro-4,6-dimethylphenylacetyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 9.0 g. (0.019 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)(=O)C>C(#N)C>[CH2:16]([O:15][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]2[N:24]=[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]3[CH:2]=2)[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccn1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)CBr
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2cn3ccccc3n2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 4-bromo-1-(3-benzyloxy-4-nitrophenyl)but-1-en-3-one (55.0 g) and 2-aminopyridine (42.3 g) in acetonitrile (380 ml) was stirred for 4 hours at ambient temperature. Ethyl acetate was added to the reaction mixture and the precipitate was collected by filtration. A mixture of water and ethyl acetate was added to the precipitate and the mixture was adjusted to pH 7.0 with 20% potassium carbonate. The precipitate was collected by filtration and washed with water to give 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]imidazo[1,2-a]pyridine (40.1 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH3:20][O:19][C:17](=[O:18])[C@H:16]([CH3:21])[NH:7][C:6]1[C:5]([CH3:8])=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: COC(=O)C(C)Br
Reactant: Cc1csc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Nc1c(C)csc1C

Procedure:
A mixture of 12.7 g (0.1 mol) 2,4-dimethyl-3-aminothiophene, 13.84 g (0.1 mol) K2CO3 and 16.7 g (0.1 mol) methyl 2-bromopropionate in 200 ml dimethylformamide are stirred over night at 80°. The mixture is cooled, filtered, evaporated, the residue dissolved in dichloromethane, washed with water, dried and evaporated to yield the title compound, m.p. 33°-34°.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[O:42]=[CH:43][CH:44](CO)O.C([BH3-])#N.[Na+]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:44][CH2:43][OH:42])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=CC(O)CO
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.2 mmol; see Example 88) in methanol (2 mL) was added glyceraldehyde (2 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (1 mmol), and the stirring was continued at RT for 10 h. The reaction mixture was then concentrated in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford 6-[4-(2-hydroxyethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)amide as a white solid. MS: m/z 565 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.Br[C:16]1[CH:26]=[CH:25][C:19]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>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:7]([C:6]1[C:2]([NH:1][C:16]2[CH:26]=[CH:25][C:19]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:18][CH:17]=2)=[N:3][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1)#[N:8]
Reactant: CN(C)C(=O)c1ccc(Br)cc1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (60 mg, 0.326 mmol), 4-bromo-N,N-dimethylbenzamide (74.3 mg, 0.326 mmol), Pd2 dba3 (14.91 mg, 0.016 mmol), K2CO3 (49.5 mg, 0.358 mmol) and X-Phos (38.8 mg, 0.081 mmol) were added to a 5 mL microwave vial. Tert-amyl alcohol (1 mL) was added and the vial was evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. overnight. Room temperature was attained, EtOAc was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-10% MeOH—CHCl3) followed by MPLC (12-100% EtOAc-hexanes) gave 4-[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]-N,N-dimethylbenzamide as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(CC(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(F)cc2)n(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.54 g ethyl 5-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate (1.7 mmol) and 0.21 g lithium hydroxide monohydrate (5.09 mmol) in 5 ml THF, 5 ml MeOH, and 2 mL water was stirred at room temperature for 2 h. The reaction was acidified with 1N HCl, was extracted with methanol/dichloromethane, dried over Na2SO4 and evaporated to provide 5-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid as a white solid. LCMS (method A) 289.2 (M+H), 287.3 (M−H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[NH:39][CH2:38][CH2:37][N:25]2[C:26](=[O:36])[C:27]2[N:28]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[N:39]([C:13]([C:12]4[C:8]([CH3:7])=[N:9][O:10][CH:11]=4)=[O:15])[CH2:38][CH2:37][N:25]2[C:26](=[O:36])[C:27]2[N:28]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1
Reactant: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3)cc1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To generate the acid chloride, oxalyl chloride (600 μL, 7.0 mmol) and DMF (1 drop) were added to 3-methyl-1,2-oxazole-4-carboxylic acid (441 mg, 3.47 mmol) in CH2Cl2 (6 mL) at 0° C. The suspension was allowed to stir 15 minutes at 0° C. followed by 1 hour at room temperature. The resulting solution was concentrated in vacuo (without heating) to give a oil that was further dried under nitrogen. To a chilled suspension of the acid chloride (generated as above, 3.47 mmol) in pyridine (3 mL) was added 10a-(4-methoxyphenyl)-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (190 mg, 0.58 mmol) in pyridine (4 mL). The reaction mixture was stirred at 0° C. to room temperature for 45 minutes and was then quenched with water (15 mL) and extracted with CH2Cl2 (4×15 mL). The organic fractions were washed with brine, dried (MgSO4), filtrated and concentrated to yield a residue that was purified by triturating with acetone to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (124) (170 mg, yield 68%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Reactant: NNc1cccc(F)c1
Product: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)cc1

Procedure:
The product was obtained starting from 4-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-30) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=426.1 (M+H)+