Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.CN([CH:25]=[O:26])C.P(Cl)(Cl)(Cl)=O.[C:32](=O)([O-])[O-:33].[Na+].[Na+]>[Cl-].[Zn+2].[Cl-].O.C1(C)C=CC=CC=1>[CH:32]([C:17]1[CH:18]=[CH:19][C:20]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([CH:25]=[O:26])=[CH:10][CH:9]=3)=[O:33]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2c3ccccc3Sc3ccccc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2c3ccc(C=O)cc3Sc3cc(C=O)ccc32)cc1

Procedure:
To 200 ml of toluene were added 20.0 g (69.1 mmol) of 10-p-tolylphenothiazine (4b), 10.0 g (73.4 mmol) of zinc chloride, and 22 ml (284.1 mmol) of DMF. The mixture was stirred, and 27 ml (289.7 mmol) of phosphorus oxychloride was gradually added thereto dropwise. The resultant mixture was reacted at 80° C. for 3 days and then poured into 300 ml of water. This mixture was neutralized with sodium carbonate, stirred at 80° C. for 2 hours, and then subjected to liquid separation. The aqueous phase was extracted with toluene three times, and the resultant organic phase collected was dried (with MgSO4) and concentrated. The residue was recrystallized twice from ethyl acetate to obtain 8.59 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2.09 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.10 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)pyridazine (hereinafter, referred to gas compound (vii) of the present invention).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:29](#[N:33])[CH:30]([CH3:32])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:30]([C:29]#[N:33])[CH3:32])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(O)C#N
Reactant: O=C(NCc1ccc(O)cc1F)c1cccnc1Oc1ccc2c(c1)OCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Yield: 26.3 %

Procedure:
To a stirred solution of 2-(benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide (5 g, 13.1 mmol), (+/−)-lactonitrile (0.93 g, 13.1 mmol) and triphenylphosphine (3.78 g, 14.4 mmol) in tetrahydrofuran (200 mL) at room temperature, diethyl azodicarboxylate (2.3 mL, 14.4 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Solvents were stripped in vacuo, diluted with ethyl acetate and washed with dilute aqueous sodium hydroxide, brine, and dried (MgSO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was purified by flash column chromatography (35% ethyl acetate/hexane), affording 1.5 g white solid (26% yield).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([F:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[F:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(Br)c(F)cc2N1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
N-(5'-bromo-4'-fluoro-2'-nitrophenyl)glycine sodium salt (0.450 g, 1.54 mmol, as prepared above) and tin (II) chloride dihydrate (1.039 g, 4.605 mmol, Aldrich, used as received) in ethanol (7.0 mL) was refluxed for 30 min. It was then cooled to room temperature and solvent was removed under vacuum. The residue was diluted with water (15.0 mL) and basified with 10% Na2CO3 to pH ~8. The resulting suspension was extracted with ethyl acetate (100 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.241 g (64%) of the title compound as a yellow powder, m.p. 214°-216° C.; 1H NMR (DMSO-d6): δ3.684 (s, 2H), 6.062 (s, 1H), 6.631 (d, 1H, J=9.3 Hz), 6.825 (d, 1H, J=6.6 Hz), 10.303 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:23][NH2:24])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:2]1([C:1](=[N:24][NH:23][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NN=C(c1ccccc1)c1ccncc1)c1cccnc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 9.16 gm (0.05 mole) of 4-benzoyl pyridine, 6.86 gm (0.05 mole) of nicotinic acid hydrazide, 100 ml of ethanol and 4.4 ml of concentrated hydrochloric acid was refluxed 16 hr. The reaction mixture was cooled to room temperature. An equal volume of water was added containing 5.4 gm (0.05 mole) of sodium carbonate. The mixture was placed in the refrigerator. The product which separated was collected, washed with water and dried to give 8.21 gm (54%) of the title compound having a melting point of 74.0° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29](#N)C>>[Br-:1].[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:29][P+:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([OH:9])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCBr
Reactant: CC#N
Product: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 86 %

Procedure:
A solution of 6-bromohexanoic acid (18 mmol, 3.50 g) and triphenylphosphine (18 mmol, 4.71 g) in acetonitrile (18 mL) was refluxed for 18 h. The reaction mixture was then cooled down, the off-white solid formed filtered. Flash chromatography over silica gel (EtOAc then MeOH) afforded the product as a white solid (1.08 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([NH2:23])=O)[NH:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:33])[NH2:23])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(c1c(Cl)ccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.70 g), Lawesson's reagent (0.77 g) and tetrahydrofuran (20 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.60 g, yield 84%) as yellow crystals. melting point 200-201° C.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:7][C:8]=1[CH2:9][CH3:10])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:24]O.[OH-].[Na+]>CCOC(C)=O.O.C1COCC1>[C:11]([C:6]1[O:7][C:8]([CH2:9][CH3:10])=[C:4]([CH2:1][CH2:2][CH2:3][OH:24])[N:5]=1)([CH3:13])([CH3:12])[CH3:14]
Reactant: C=CCc1nc(C(C)(C)C)oc1CC
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1oc(C(C)(C)C)nc1CCCO
Reaction time: 3 h

Procedure:
0.693 g of 4-allyl-2-tert-butyl-5-ethyl-oxazole (3.585 mmol) was dissolved under an argon atmosphere in 10 ml of abs. THF and treated at 0° with 3 eq. of 9-BBN (0.5 M, hexane). After 3 h at ambient temperature, when TLC indicated the absence of starting material, 20.9 ml of 30% H2O2 and 10. 3 ml of 3N NaOH was added dropwise, but simultaneously. After cessation of the strongly exothermic reaction, the mixture was diluted with AcOEt and water, the layers separated, the aqueous phase reextracted with AcOEt, and the combined organic phases washed with water. Drying over sodium sulfate and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=1/1) afforded 0.400 g of 3-(2-tert-butyl-5-ethyl-oxazol-4-yl)-propan-1-ol as colorless oil.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][C@@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:14][C@@H:13]2[F:18])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: F[C@H]1CN(c2ncc(C(F)(F)F)cn2)CC[C@H]1NC1CC1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-trifluoromethyl-pyrimidine following a procedure analogous to that described for Intermediate 87.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:17]([O:19]CC)=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCO.Cl>C1COCC1.O>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate from Step A (2.48 g, 8.15 mmol) and 1.0 N sodium hydroxide (8.96 mL, 8.96 mmol) in THF (50 mL), H2O (10 mL), and EtOH (20 mL) was stirred at ambient temperature for 18 h. The mixture was acidified with hydrochloric acid to about pH 3 and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, to give the title compound. MS: m/z=340 (M+Na+CH3CN).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[N:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(NCCNc2nc(Br)cn3ccnc23)nc1
Temperature: 140 °C

Procedure:
8 g (28.9 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine were dissolved in 80 ml of DMSO, and 16.1 ml (115.6 mmol) of triethylamine and 5.154 g (31.78 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 2A) were added. The mixture was heated at 140° C. in a microwave for 1.5 h. The solution was poured into water and the precipitate was filtered off. Washing with water and drying under high vacuum gave 10.3 g (94% of theory) of the product as a solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O1CCOCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-fluoro-2-nitrobenzenamine (3.0 g, 18.1 mmol), triethylamine (5.0 mL, 36.3 mmol), and 1-methylpiperazine (2.0 mL, 18.1 mmol) in dioxane (25 mL) was heated at reflux for 18 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue dissolved in DCM (100 mL). This solution was washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g) as a dark brown solid. A solution of 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g; 13.7 mmol) in absolute ethanol (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.30 g; 2.7 mmol) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (2.36 g).
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([N:51]5[CH:55]=[CH:54][CH:53]=[N:52]5)=[CH:47][C:46]=4[C:56]([F:59])([F:58])[F:57])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[N:51]1([C:48]2[CH:49]=[CH:50][C:45]([CH2:44][NH:43][C:41]([N:38]3[CH2:37][CH2:36][CH:35]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]5[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=5)=[CH:61][CH:60]=4)[CH2:40][CH2:39]3)=[O:42])=[C:46]([C:56]([F:58])([F:57])[F:59])[CH:47]=2)[CH:55]=[CH:54][CH:53]=[N:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(-n5cccn5)cc4C(F)(F)F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(-n2cccn2)cc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 65 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-[4-(1H-pyrazol-1-yl)-2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide (0.18 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.09 g, 0.13 mmol)
Reaction SMILES: CO[C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NCC[CH2:42][S:43]([OH:46])(=[O:45])=[O:44]>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][CH2:42][S:43]([OH:46])(=[O:45])=[O:44])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: NCCCS(=O)(=O)O
Product: O=C(NCCCS(=O)(=O)O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 35, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 3-amino-1-propanesulfonic acid (commercially available, CAS RN 3687-18-1). Brown solid (18%). MS (ESI): m/z=605.102 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[F:39]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[C:33]([F:39])[CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Fc1cc(Cl)ccc1CBr
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cl)cc2F)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-chloro-2-fluoro-benzene following the procedure of Example 478: MS (ESI) m/z 536.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[Br:19]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)=[O:11]
Reactant: BrBr
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2Br)CC1
Reaction time: 7 h

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.222 g) in acetic acid (1 mL) at ambient temperature was treated with bromine (0.05 mL) and stirred for 7 h. The reaction mixture was poured into water and adjusted to basic pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane, afforded the title compound (0.154 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([NH:36][CH3:37])=[O:35]>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][N:24]([CH2:33][C:34]([NH:36][CH3:37])=[O:35])[C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Reactant: CNC(=O)CBr
Agent: Cc1ccc(F)c(-c2cc(Nc3ccnc4c[nH]nc34)c(C)cn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 85 °C

Procedure:
A mixture N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (54 mg, 0.162 mmol) and Cs2CO3 (52.6 mg, 0.162 mmol) were stirred in DMF (2 mL) for 5 minutes. 2-Bromo-N-methylacetamide (24.55 mg, 0.162 mmol) was added; the vessel was sealed and heated in a microwave at 85° C. for 35 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-30% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give 2-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)-N-methylacetamide: 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.46 (s, 3H) 2.58 (s, 3H) 2.78 (s, 3H) 5.23 (s, 2H) 7.01 (d, J=4 Hz, 1H) 7.30-7.42 (m, 1H) 7.56-7.67 (m, 1H) 7.96 (s, 1H) 8.32 (d, J=4 Hz, 1H) 8.45 (s, 1H) 8.52 (s, 1H); MS [M+H] found 406.4; and 2-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)-N-methylacetamide; 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.42 (s, 3H) 2.54 (s, 3H) 2.75 (s, 3H) 5.24 (s, 2H) 7.29-7.41 (m, 2H) 7.52-7.59 (m, 1H) 7.61 (d, J=4 Hz, 1H) 8.18 (s, 1H) 8.40 (s, 2H); MS [M+H] found 406.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:9])\[CH3:16])[CH3:11]
Reactant: Oc1cccc(Br)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1F
Yield: 69.5 %

Procedure:
To a stirred mixture of 3-bromo-2-fluoro-phenol (19.5 g, 0.102 mol) and ethyl-2-butynoate (22.0 g, 0.196 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15.6 g, 0.102 mol) slowly. After addition was complete the mixture was stirred at reflux for overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated, and the residue dried under high vacuum which afforded (E)-3-(3-bromo-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (21.5 g, 69%) and used without further purification.
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[C:4]#[C:5][CH2:6][OH:7])[CH3:2].CCOCC.C1COCC1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2]
Reactant: CCC(O)(C#CCO)CC
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/CO)CC
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A 3 liter, round-bottom flask equipped with a mechanical stirrer, dropping funnel, thermometer and nitrogen bubbler was charged with 168 g of crude 4-ethyl-2-hexyn-1,4-diol TES-ether and 1 liter of THF. After cooling to −70° C. with a dry ice-acetone bath, 200 mL (600 mmol) 65+wt. % solution of Red-Al® in toluene was added slowly to control vigorous gas evolution and foaming during addition of the first 50% of the reagent. Then, the mixture was warmed to 0° C. with an ice bath and stirred for 1 hour. TLC analysis indicated complete reaction. The mixture was cooled to −70° C. and carefully quenched by the addition of 240 mL of 30% ammonium hydroxide solution, while maintaining the internal temperature below −50° C. The mixture was concentrated under reduced pressure to remove the THF and the resulting slurry was diluted with 400 mL of diethyl ether. The solid was removed by filtration and washed twice with 200 mL of diethyl ether. The combined filtrate and washes were washed twice with 200 mL of water and twice with 200 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure, then under high vacuum to give 160 g of crude (E)-4-ethyl-2-hexen-1,4-diol TES-ether as a pale yellow viscous liquid. This material was used directly in the next step without further purification.