Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]
Reactant: COc1ccc(CO)cn1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: COc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)cn1

Procedure:
Prepared by the method of Example 31 using (6-methoxy-3-pyridinyl)methanol (0.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:46](Cl)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:46]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:48])=[O:47])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)N2CCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 75 mg) at room temperature, and the mixture was stirred for 15 min. 15-Crown-5 (410 mg) was added, pyrrolidine-1-sulfonyl chloride (210 mg) was added and the mixture was further stirred for 6 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a colorless oil (yield 260 mg, 92%).
Reaction SMILES: C[N:2]([CH3:16])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[O:17]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1CN)[CH3:18]>CN1C(=O)N(C)CCC1>[CH3:18][O:17][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:16][N:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)[C:7]1=[NH:8]
Reactant: CN(C)/C=C/c1cc([N+](=O)[O-])ccc1C#N
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1

Procedure:
(E)-2-(2-(Dimethylamino)vinyl)-4-nitrobenzonitrile (4.6 g, 21.2 mmol) and 2,4-dimethoxylbenzylamine (4.0 mL, 1.25 equiv) in DMPU (10 mL) were heated at 140° C. for 3 h. The solvent was removed by vacuum distillation and residue was treated with hexanes/ethyl acetate (1:1). The solid was collected by filtration and washed with hexane to give 2-(2,4-dimethoxybenzyl)-6-nitroisoquinolin-1 (2H)-imine (4.6 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H) 3.81 (s, 3 H) 4.96 (s, 1 H) 6.28 (d, J=6.59 Hz, 1 H) 6.46 (d, J=7.47 Hz, 1 H) 6.58 (d, J=1.76 Hz, 1 H) 7.03 (d, J=8.79 Hz, 1 H) 7.27 (d, J=6.15 Hz, 1 H) 8.02 (dd, J=9.01, 2.42 Hz, 1 H) 8.31 (d, J=2.20 Hz, 1 H) 8.43 (d, J=8.35 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Br)[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([NH2:19])[N:3]=1.[NH3:20]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([NH2:20])[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([NH2:19])[N:3]=1
Reactant: N
Reactant: Nc1nc(N)c2nc(Br)n(COC(CO)CO)c2n1
Solvent: CO
Product: Nc1nc(N)c2nc(N)n(COC(CO)CO)c2n1
Temperature: 125 °C

Procedure:
A mixture of 1.153 g (3.46 mM) of 2-[(2,6-diamino-8-bromo-9H-purin-9-yl)methoxy]-1,3-propanediol and 300 ml of a saturated solution of ammonia in methanol was heated at 125° C. in a Parr bomb for 18 hours. The reaction mixture was purified by flash chromatography on silica gel eluting with a methanol dichloromethane gradient (10→40%) to give a light brown solid. This solid was recrystallized from acetonitrile/methanol to yield the title compound as a light brown powder, mp 206°-208° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[ClH:36]>O1CCOCC1>[Cl:36][C:14]([CH3:15])([CH3:16])[CH2:13][CH2:12][C:5]1([CH3:17])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18]
Reactant: CC(C)=CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: Cl
Solvent: C1COCCO1
Product: CC(C)(Cl)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
To a solution of Example 139 (40 mg, 0.078 mmol) in dioxane (3 mL) was added a solution of 6N aqueous hydrochloric acid (3 mL). The mixture was heated at 65 C for 3 hours, and the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% trifluoroacetic acid in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min to provide the title (4 mg, 9%). MS (ESI) m/z=550 (M−H)+. 1H NMR (300 MHz, DMSO-d6): δ 0.96 (m, 1H), 1.24 (m, 1H), 1.40 (s, 3H), 1.42 (s, 3H), 1.60 (s, 3H), 2.29 (m, 1H), 2.42 (m, 1H), 3.08 (s, 3H), 7.56 (m, 3H), 7.73 (m, 3H), 8.16 (d, J=7.4 Hz, 1H), 10.24 (s, 1H), 13.81 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:27][N:26]2[C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn(-c2ccc(OC)cc2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 39.6 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (5.00 g, 16.3 mmol) was combined with 4-methoxyphenylhydrazine hydrochloride (4.00 g, 22.9 mmol) and sodium acetate (4.01 g, 48.9 mmol) in xylenes (30 mL). The reaction mixture was heated to 135° C. for 36 hours using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with water (50 mL) and 1N aqueous hydrochloric acid (50 mL). The organic extract were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 2.14 g of 6-bromo-3-ethyl-1-(4-methoxy-phenyl)-1H-indazole (40% yield). 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3, J=7.7), 3.00 (q, 2, J=7.7), 3.86 (s, 3), 7.03 (d, 2, J=8.9), 7.25 (dd, 1, J=8.5, 1.5), 7.53 (d, 2, J=9.1), 7.58 (d, 1, J=8.5), 7.73 (d, 1, J=1.5). 13C NMR (100 MHz, CDCl3) δ 13.53, 20.34, 55.61, 113.02, 114.70, 121.33, 121.70, 122.45, 123.93, 124.50, 132.90, 140.67, 148.83, 158.42. IR 2970, 2934, 1604, 1519, 1461, 1442, 1300, 1250, 1050, 1035, 945, 832 cm-1. Analysis calculated for C16H15BrN2O: C, 58.02; H, 4.56; N, 8.46. Found: C, 58.39; H, 4.69; N, 8.13.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 4.0 g. (0.0125 mole) of ethyl 5-(ρ-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 26 ml. of 0.5N sodium hydroxide (0.013 mole) is heated under reflux for 30 mins. The resulting solution is acidified with dilute hydrochloric acid, and the precipitated solid is collected by filtration, air dried and recrystallized from 2-propanol to give 5-(ρ-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid as a white crystalline solid, M.P. 178°-179° C.
Reaction SMILES: [F:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)([F:5])[CH2:3]I.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)([F:5])[F:1])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(F)(F)CI)nc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)CN=[N+]=[N-])nc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
A solution of 2-(1,1-Difluoro-2-iodo-ethyl)-5-methyl-pyridine (3.8 g, 13.43 mmol), as prepared in the previous step, was dissolved into DMSO (6 mL), treated with NaN3 (1.0 g, 16.12 mmol, 1.2×) and heated to 90° C. After 2 days, the reaction was partitioned between EtOAc (125 mL) and H2O (2×50 mL). The organic phase was dried over Na2SO4 and concentrated to afford the product as a clear oil (2.46 g, 12.42 mmol, 93% crude yield). 1H NMR (300 Hz, CDCl3) δ 8.49 (s, 1H), 7.63 (m, 2H), 4.01 (t, J=13.2 Hz), 2.41 (s, 3H); LC/MS (m/z) [M+1−N2]+ 171.1 (calculated for C8H9F2N2, 171.2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](=O)[CH2:13][C:14]([O:16]C)=O.[CH3:19][NH:20][NH2:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]1[NH:21][N:20]([CH3:19])[C:14](=[O:16])[CH:13]=1
Reactant: CNN
Reactant: COC(=O)CC(=O)Cc1ccc(OC)c(Cl)c1Cl
Product: COc1ccc(Cc2cc(=O)n(C)[nH]2)c(Cl)c1Cl

Procedure:
46.2 g (0.16 mol) of methyl 4-(2,3-dichloro-4-methoxyphenyl)-3-oxobutyrate and 8.1 g (0.18 mol) of methylhydrazine were reacted by the method of Example 1. Yield: 30.8 g;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:17](SC1C=CC=CC=1)[C:18]([NH2:20])=[O:19]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: NC(=O)C(Sc1ccccc1)c1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Yield: 78.3 %

Procedure:
To an agitated solution of 28.5 g (0.077 mole) of 2-amino-3-(4-chlorobenzoyl)-α-(phenylthio)phenylacetamide in 1 liter of tetrahydrofuran was added 230 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). After 15 minutes the mixture was filtered and the filtrate concentrated under reduced pressure to give 17.4 g (84%) of yellow crystalline solid. Recrystallization from isopropyl alcohol followed by recrystallizing twice from absolute ethanol gave yellow needles, m.p. 212°-215° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)[CH3:2].[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:17]([NH2:18])=[O:16])[CH:10]=1)[CH3:2]
Reactant: CCn1cccc1Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cccc1Cc1cccc(NC(N)=O)c1
Reaction time: 72 h
Yield: 65.2 %

Procedure:
1-Ethyl-2-(3'-aminobenzyl)pyrrole 5.6 g (28 mmol) was dissolved in a mixture of 500 ml of methylene chloride and 100 ml methanol; 3.92 g (60 mmol) of sodium cyanate were added to the solution and thereafter, in a dropwise fashion and at room temperature, 4.6 ml (59 mmol) of trifluoroacetic acid in 100 ml of methylene chloride. When the addition was completed, the resulting mixture was stirred for 72 hours, 10 g (90 mmol) of sodium carbonate were added thereto, the mixture stirred for 15 minutes and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using methylene chloride-acetone (85:15) as eluant, to produce 4.44 g (65%) of the title compound, 1-ethyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:16][C:9]=23)[CH:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)[NH:4]1)[CH3:2].[CH3:37][NH:38][CH3:39].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:37][N:38]([CH2:23][C:19]1[CH:18]=[C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[C:5]([C:25]5[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=5)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:39]
Reactant: CCN1C=C(c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)C(c2ccc(NC(=O)N(C)C)cc2)N1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N′-(4-{1-ethyl-4-[2-(3-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-2H-pyrazol-3-yl}phenyl)-N,N-dimethylurea (11.45 g, 23.9 mMol) was added a solution of 2 M dimethylamine in THF (24 mL, 48 mMol). The slurry was rinsed down with THF (150 mL) and treated with NaBH(OAc)3 (8.6 g, 40.6 mMol). (Gentle gas evolution was seen and the reaction got slightly warm to the touch.) The reaction was stirred at RT for 1 h (started out as a thick suspension that slowly became a homogeneous fine suspension) and concentrated to dryness under vacuum. The residue that remained was basified with aq. 1 N Na2CO3, (200 mL) and aq. 1 N NaOH (25 mL), extracted with CHCl3 (300 mL) washed with brine, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O/pet. ether, filtration, and drying under vacuum gave the title compound (11.20 g, 92%) as a yellow solid (>95% pure by HPLC): MS (ES) m/e 508.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6)12.14 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=4.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.27 (dd, 1H), 6.79 (d, J=5.1 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H), 3.43 (s, 2H), 2.18 (s, 6H), 1.51 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:7][CH:8]=1)[NH2:2].[CH3:15][C:16]([CH3:18])=O>>[C:16](=[N:2][NH:1][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:7][CH:8]=1)([CH3:18])[CH3:15]
Reactant: Cc1nccn1-c1ccc(NN)nn1
Reactant: CC(C)=O
Product: CC(C)=NNc1ccc(-n2ccnc2C)nn1

Procedure:
3.0 g (15.8 millimoles) of 3-hydrazino-6-(2-methyl-imidazol-1-yl)-pyridazine are suspended in 40 ml of acetone and the suspension is heated for 10 minutes on a steam bath under reflux.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:4][CH:3]=1.CN(C)[CH:16]=[C:17]([N:23]=[CH:24]N(C)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[C:11]3[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:23]=[CH:24][C:10]=3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2cccc2)cc1
Reactant: CCOC(=O)C(=CN(C)C)N=CN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(ccn2Cc2ccc(F)cc2)cn1
Yield: 19 %

Procedure:
A solution of 1-(4-fluorobenzyl)-1H-pyrrole (11.1 g, 63.4 mmol), ethyl 3-dimethylamino-2-(dimethylamino-methyleneamino)-acrylate (14.84 g, 69.7 mmol) [prepared according to W. Kantlehner, F. Wagner, H. Bredereck, Liebigs Ann. Chem. 1980, 344-357] and trifluoroacetic acid (19.4 mL, 253.6 mmol) in acetic acid (80 mL) was stirred for 16 h at ambient temperature. Then the solution was heated to reflux for 4 hr. After cooling down, it was concentrated. The residue was poured into satd. potassium carbonate solution (1000 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried over sodium sulfate, and concentrated. Purification by column chromatography with toluene:acetonitrile (2:1) provided the title compound. (3.6 g, 19% yield). 1H NMR (CDCl3) δ ppm 9.15 (s, 1H), 8.23 (s, 1H), 7.37 (d, 1H, J=3.0 Hz), 7.0-7.11 (m, 4H), 6.83 (d, 1H, J=3.0 Hz), 5.40 (s, 2H), 4.52 (q, 2H, J=7.0 Hz), 1.48 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 299.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:21][CH:20]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-fluorobenzeneboronic acid: MS (ESI) m/z 306 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.02 (8H, m), 3.89 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.30(3H, s), 2.27 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.C(OC([N:26]1[CH2:31][CH2:30][C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.Cl>C(#N)C>[CH2:30]1[C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][N:26]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1ncnc(N2CCC3(CCNCC3)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 1.0 g (3.87 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.18 g (4.6 mmol) 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester using 1.97 mL (11.6 mmoL) DIPEA in 20 mL acetonitrile. The reaction mixture is stirred at 80° C. over night. 1.6 ml conc. HCl is added the reaction is stirred for 4 hours at 80° C. The solvent is removed under reduced pressure. The residue is taken up to in acetonitrile and K2CO3 is added. The mixture is stirred at 80° C. over night. The solvent is removed and the residue is taken up in DCM/water. After phase separation the organic phase is extracted twice with DCM. The combined organic layers are dried over Na2SO4, filtered and the solvent is removed under reduced pressure yielding 1.08 g (74%) of crude product, which is used without further purification in the next step.
Reaction SMILES: O1CCCC1.[C:6]1([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[C:6]1([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=4)[O:23][N:22]=3)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)Cc1ccc(CNc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(CNc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylaminomethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 73-1-6 and 3-ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (104 pit, 0.748 mmol), which was stirred for 7 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1-1:2) to obtain the title compound (11 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[Br:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[S:18][C:19]=1[Cl:20]>>[Br:14][C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][C:4]3[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=3[N:6]=2)(=[O:23])=[O:22])[S:18][C:19]=1[Cl:20]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Product: CC1(C)CC(=O)c2sc(NS(=O)(=O)c3cc(Br)c(Cl)s3)nc2C1

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)one (53 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white-yellow solid (47.1 mg) with purity >90%: MS (pos) m/z 455.2, 457.2.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.87 min, m/z=459.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:12]1[CH:13]=[CH:14][C:2]([Cl:1])=[C:3]([CH:11]=1)[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H](C)Oc1cc(CBr)ccc1Cl

Procedure:
To (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate (2.4 g, 10.5 mmol) in CCl4 (20 mL) was added NBS (1.92 g, 11.55 mmol) and AIBN (0.35 g, 2.1 mmol). The mixture was refluxed overnight. The reaction mixture was cooled and the solvent was removed to obtain the crude. The crude was purified by flash chromatography (AcOEt/Hexane 0˜30%) to obtain the title compound.