Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.S(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:21][C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[S:11][N:10]=1
Reactant: O=c1[nH]sc2c([N+](=O)[O-])cccc12
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 86 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 98.1 g (0.5 mol) of 7-nitro-1,2-benzisothiazol-3-one, 146.2 g (2 mol) of N,N-dimethylformamide and 500.0 g of chlorobenzene. While stirring, 119.0 g (1.0 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from toluene to give 91.2 g (0.43 mol) of 3-chloro-7-nitro-1,2-benzisothiazole. The yield based on 7-nitro-1,2-benzisothiazol-3-one was 85%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([I:33])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Yield: 29.7 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (459 mg) and NIS (343 mg) in DCM (13 mL) was refluxed overnight; then concentrated, the residue was column purified to give the desired product (184 mg). LC MS ESI: 488 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:52]([O:51][C@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)c5)c4)cc23)c1
Temperature: 55 °C
Yield: 60.4 %

Procedure:
A mixture of Intermediate 98 (0.35 g, 0.48 mmol) and Intermediate 2 (0.24 g, 0.72 mmol) in DMF (4.5 mL) was treated with N,N-diisopropylethylamine (0.25 mL) and catalytic potassium iodide (50 mg). The mixture was heated for 19 hours in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 25 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound as a yellow solid (0.28 g, 61%). ES/MS calcd. for C53H57N6O8SSi+ 965.4. Found m/z=965.5 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:24]([C:25](OC)=[O:26])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([C:13]2[C:24]([CH2:25][OH:26])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1c(-c2ccccc2)nn2ccc3occc3c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(-c2ccccc2)nn2ccc3occc3c12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a suspension of 80% lithium aluminum hydride (294 mg, 6.35 mmol) in tetrahydrofuran (10 mL) was added a solution of methyl 2-phenylfuro[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (465 mg, 1.59 mmol) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at 50° C. for 5 min. Sodium sulfate decahydrate (4.3 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by recrystallization (ethyl acetate) to give the title compound (367 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:30]1(=[O:36])[NH:35][CH2:34][CH2:33][CH2:32][CH2:31]1.NC1CCCCC1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(OC(=O)C)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]5=[O:36])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCCN1
Reactant: O=C1c2c(c(C(F)(F)F)nn2-c2ccc(F)c(Cl)c2)CCN1c1ccc(I)cc1
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCCCN1c1ccc(N2CCc3c(C(F)(F)F)nn(-c4ccc(F)c(Cl)c4)c3C2=O)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 80.9 %

Procedure:
Part B. 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.54 g, 1.0 mmol), δ-valerolactam (0.12 g, 1.2 mmol), 1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), K3PO4 (0.42 g, 2 mmol) and CuI (2 mg, 0.01 mmol) were added to 5 mL of 1,4-dioxane. The mixture was degassed under argon and stirred at 110° C. under N2 for 48 h. The mixture was then cooled to rt. The dioxane was removed. The residue was dissolved in EtOAc (100 mL), washed with HCl (1N, 30 mL), water (50 mL×2), and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified via flash chromatography on silica gel using 1:2 hexane:ethylacetate to give the desired product (0.41 g, 80% yield). LRMS (ES+): 507.1 (M+H)+. 1H NMR (CDCl3) δ 7.68-7.65 (m, 1H), 7.50-7.45 (m, 1H), 7.36-7.16 (m, 5H), 4.16 (t, 2H), 3.64-3.62 (m, 2H), 3.47 (br, 3H), 3.17 (t, 2H), 2.62 (t, 2H), 1.98-1.96 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][C@H:5]([OH:7])[CH3:6].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.O>CN(C=O)C>[CH3:6][C@@H:5]([O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[CH2:4][CH2:3][O:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C[C@@H](O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCOc1ccc(C#N)cc1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Sodium hydride (3.18 g, 133 mmol) was dispersed in 100 ml DMF and added with 1,3-(R)-butanediol (5.03 g, 55.8 mmol) while being cooled with ice. The mixture after being cooled with ice for another one hour was stirred at room temperature for 2 hours and then added with 4-chlorobenzonitrile (16.8 g, 122 mmol) at room temperature, followed by being reacted for 20 hours. After completion of the reaction, the reaction mixture was carefully added with 5 ml water to inactivate excess sodium hydride, followed by distilling out DMF in vacuum. The resulting mixture after being added with 200 ml of water was subjected to processes of extraction of an organic matter with ethyl acetate, washing with a solution of saturated sodium chloride and distillation of the solvent, followed by distillation of the oily residue thus obtained using Kugelloa distilling equipment at a temperature of 275° C. and a pressure of 0.5 mmHg thereby obtaining the intended product (13.3 g, 45.4 mmol, 81%).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:17][N:13]2[C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:41])=[O:2])=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1cccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
To a mixture of 3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (20.0 mg, 0.03 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (19.5 mg, 100%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1473.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(=S)=S>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
294 g of aluminium chloride was added to 1000 ml of carbon disulfide and stirred. The reaction solution was cooled to 0° C. or lower, and 166 g of propionyl chloride was dropwise added thereto. Next, 283 g of bromobenzene was dropwise added thereto. Then, the whole was stirred for one hour at room temperature. After reaction, the reaction solution was poured into a mixture of 300 ml of concentrated hydrochloric acid and 600 g of ice. This was extracted with chloroform and washed three times with water, and chloroform was removed by distillation. By distillation under reduced pressure (b.p. 100° to 105° C./2 mmHg), 301 g of 1-bromo-4-propionylbenzene was obtained.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22]O)[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22][I:1])[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: COc1cccc2c(=O)n(CCCO)c(COc3ccc(Cl)cc3)nc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c(=O)n(CCCI)c(COc3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
Iodine (1016 mg, 4 mmol) was added to a mixture of the product from Step A above, triphenylphosphine (1050 mg, 4 mmol) and imidazole (545 mg, 8 mmol) in toluene (20 mL) at 0° C. The reaction mixture was slowly allowed to warm to room temperature and was stirred for 17 h and diluted with CHCl3. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was chromatographed on SiO2-gel using 30% EtOAc/hexanes to yield the product as a yellow oil (450 mg, 35%). API-MS: 485 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.35 (t, 1 H), 7.2 (d, 2 H), 7.1 (d, 1 H), 6.9 (d, 2 H), 5.15 (s, 2 H), 4.1 (t, 2 H), 3.93 (s, 3 H), 3.9 (s, 3 H), 3.15 (t, 2 H), 2.23 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[C:7]=1[OH:8]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 84.4 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.50 g, 1.4 mmol) and 2-naphthoyl chloride (0.27 g, 1.4 mmol) were dissolved in 1,4-dioxane (10 ml) and the solution heated under reflux for 4 hr. Solvent was evaporated under reduced pressure and the product purified by column chromatography on silica gel (eluent, hexan-ethyl acetate, 8:2) to furnish the title compound (0.60 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N)cc1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A pressure flask was charged with a suspension of tert-butyl 2-(4-nitrophenyl)propan-2-yl-carbamate (4.62 mmol) in ethanol (20 mL) and palladium on carbon (100 mg). The flask was placed on a Parr shaker, purged with H2 (30 psi), and stirred overnight. The crude product was filtered through celite, concentrated, and chromatographed (hexane:ethyl acetate) to obtain the desired product (420 mg, 36% over two steps) as an orange-red oil: 1H NMR (300 MHz, CDCl3) δ 7.26-7.17 (m, 2H), 6.67-6.62 (m, 2H), 4.82 (s, 1H), 1.60 (s, 3H), 1.57 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:77][CH:78]1[CH2:82][CH2:81][N:80]([C:83]([NH2:85])=[O:84])[CH2:79]1>O1CCOCC1.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].CN(C=O)C>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:85][C:83]([N:80]4[CH2:81][CH2:82][CH:78]([OH:77])[CH2:79]4)=[O:84])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1
Reactant: NC(=O)N1CCC(O)C1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(O)C4)c3)cc2n1
Temperature: 110 °C
Yield: 60.4 %

Procedure:
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (400 mg, 0.92 mmol) was suspended in dioxane (15 mL) and treated consecutively with DMF (5 mL), Pd2dba3 (19 mg, 0.02 mmol), Xantphos (32 mg, 0.06 mmol), cesium carbonate (358 mg, 1.1 mmol) and 3-hydroxy-pyrrolidine-1-carboxylic acid amide (358 mg, 2.75 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give 3-hydroxy-pyrrolidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (270 mg, 61%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 8.62 (1H, s), 8.25 (1H, s), 8.14 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.90 (1H, s), 7.71-7.73 (1H, m), 7.64 (1H, d), 7.23-7.33 (2H, m), 6.93-6.95 (1H, m), 6.67 (1H, t), 6.53 (1H, d), 4.93 (1H, d), 4.43 (2H, d), 4.26 (1H, m), 4.13 (3H, s), 3.40-3.48 (4H, m), 1.79-1.94 (2H, m); m/z (ES+) 486 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11](Cl)[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2].O.O.[SH-:19].[Na+].Cl.[OH-].[Na+]>O>[C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11]([SH:19])[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2]
Reactant: [SH-]
Reactant: O=C(O)CCn1nc2ccc(Cl)nn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1nc2ccc(S)nn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-carboxyethyl)-6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (567 mg., 2.34 m.moles) and 70% sodium hydrosulfide dihydrate (924 mg., 7.02 m.mole) in water (10 ml.) was stirred at room temperature for two hours. The reaction mixture was adjusted successively to pH 1 with c. HCl, to pH 10 with NaOH and then to pH 1 with c. HCl. The rsulting precipitate of 2-(carboxyethyl)-2,3-dihydro-6-mercapto-s-triazolo[4,3-b]pyridazin-3-on was collected by filtration and washed with water. Yield: 418 mg. (74%). M.p. 174°-176° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:21]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:21][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Under a nitrogen atmosphere, N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (4.0 g, 16 mmol) (i.e. the product of Example 13, Step A) in tetrahydrofuran (25 mL) was cooled to −78° C. was then treated with n-butyllithium (2 M solution in cyclohexane, 8.6 mL, 17.2 mmol) dropwise. The reaction mixture formed a thick precipitate, and stirring was continued for 30 minutes after the addition. To the stirred suspension, a solution of hexachloroethane (4.2 g, 18 mmol) in tetrahydrofuran (15 mL) was added dropwise. After 1 h the resulting clear solution was warmed to ambient temperature and quenched with the addition of water (50 mL). The reaction mixture was extracted with dichloromethane and dried over MgSO4. The reaction mixture was filtered and concentrated under reduced pressure to give 4.38 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+:6].C(O[C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH2:11][CH3:12])C>C(O)C>[C:2]([N-:3][C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH2:11][CH3:12])#[N:1].[Na+:6]
Reactant: N#CN
Reactant: CCOC(CC)=C(C#N)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC([N-]C#N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In portions, 7.56 g of cyanamide are added to a solution of 32.38 g (33.4 ml, density=0.97 g/l) of 30% sodium methanolate solution and 100 ml of ethanol and the mixture is stirred at 25° C. for ca. 5 minutes; then, over the course of ca. 25 minutes, 30 g (ca. 90% strength, 180 mmol) of (1-ethoxypropylidene)malononitrile are added dropwise. The mixture is stirred for two hours, then the volatile constituents are largely removed by distillation, and the remaining residue is taken up in methylene chloride. The methylene chloride phase is separated off and the remaining 37.57 g of sodium cyano[1-(dicyanomethylidene)propyl]azanide with ca. 80% purity are used in the following stage.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1>CC(C)CO>[CH2:4]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: Nc1cc(OCC2CC2)ncn1
Solvent: CC(C)CO
Product: CC(C)COc1cc(N)ncn1
Yield: 76 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where 2-methylpropan-1-ol was used as the alcohol. 6-isobutoxypyrimidin-4-amine (0.196 g, 1.172 mmol, 76% yield) was obtained as a white solid. m/z (ESI) 168.2 (M+H)+.