Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCC[CH:2]1[N:7]=C=O.[NH2:10][CH:11]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:12][N:13]1[CH2:20][CH:19]2[CH2:21][CH:15]([CH2:16][N:17]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:14]1>C1C=CC=CC=1>[C:2]([NH:10][CH:11]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:12][N:13]1[CH2:14][CH:15]2[CH2:21][CH:19]([CH2:18][N:17]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:16]2)[CH2:20]1)(=[O:1])[NH2:7]
Reactant: CC(C)OC(=O)N1CC2CC(CN(CC(N)c3ccc(C#N)cc3)C2)C1
Reactant: O=C=NC1CCCCO1
Solvent: c1ccccc1
Product: CC(C)OC(=O)N1CC2CC(CN(CC(NC(N)=O)c3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of tetrahydro-2-pyranyl isocyanate (382 mg, 3.0 mmol) in benzene (10 mL) was added to a stirred solution of iso-propyl 7-[2-amino-2-(4-cyanophenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (see Example 9 above; 1.07 g; 3.0 mmol) in benzene (35 mL). The reaction mixture was stirred for 2 h at rt, after which the solvent was evaporated and the residue re-dissolved in a mixture of MeOH (27 mL) and dilute HCl (4.5 mL; 0.1 M). The resulting solution was refluxed for 3 h, before the acid was neutralized (NaHCO3) and the MeOH removed by evaporation to give a precipitate which was collected and recrystallized from IPA to give the title compound in 67% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH2:36])=[S:35]>>[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:36][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:35]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccccc1NC(N)=S
Product: Cc1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(o-tolyl)thiourea and isolated as an off-white solid (0.148 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19][CH3:20])[CH:16]=[C:15]([CH3:21])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][CH2:20][S:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:6]([CH3:7])[CH3:8])[CH:9]([CH3:10])[CH3:11])=[C:15]([CH3:21])[CH:16]=1
Reactant: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(SCCl)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methylsulfanyl-phenoxy)triisopropylsilane (2.18 g, 6.72 mmol) in CCl4 (25 mL) at room temperature was added N-chlorosuccinimide (0.99 g, 7.39 mmol). The reaction mixture was stirred at room temperature for 16 hrs and filtered through a Celite plug. The solvent was removed under reduced pressure to afford crude (4-chloromethylsulfanyl-2,6-dimethylphenoxy)triisopropylsilane as an oil (2.4 g, 100%). This crude oil was dissolved into phosphorous acid triethyl ester (1.5 mL). It was heated at 180° C. for 30 min by microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-phenylsulfanyl)methylphosphonate as a yellow oil (1.6 g, 52%): 1H NMR (200 MHz, DMSO-d6): δ 7.09 (s, 2 H), 4.98 (m, 4 H), 3.31 (d, J=13.8 Hz, 2 H), 2.17 (s, 6 H), 1.25 (m, 9 H), 1.09 (d, J=7.0 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate/Hexanes (2:3); Rf=0.45.
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[O-]CC.[Na+].[Na].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CS(C)=O.C(O)C>[CH2:28]([O:27][C:25]([CH:24]([O:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=2)[N:3]=1)[CH3:30])=[O:26])[CH3:29]
Reactant: Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(C)Br
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Eleven g of 3-hydroxy-1-(4-trifluoromethoxyphenyl)-1,2,4-1H-triazole was dissolved in 100 ml of dimethylsulfoxide, and to it was added a solution of sodium ethoxide prepared from 1.2 g of sodium and 20 ml of absolute ethanol. An additional 100 ml of dimethylsulfoxide was added, and the solution was heated on the steam bath for 90 minutes. Then 8.3 g of ethyl 2-bromopropionate was added, and heating was continued for 90 minutes more. The solution was cooled and poured over ice water, and the solid was collected and dried to obtain 15 g of the desired product, m.p. 52°-53°.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]1=[O:13]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 20 g of 3-bromo-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine in 50 ml of dimethylformamide at 65° is added to a suspension of 114.7 g of potassium carbonate in 200 ml of dimethylformamide at room temperature maintaining the temperature of the reaction mixture below 30°. The reaction mixture is then stirred at room temperature for 90 minutes. A solution of 20.7 g of ethyl bromoacetate in 50 ml of dimethylformamide is added over a period of 30 minutes at room temperature. The reaction mixture is then stirred at 55° for one hour, filtered, the filter cake is washed with 100 ml of dimethylformamide, and the filtrate is evaporated to a small volume (removing about 200 ml of dimethylformamide) at 65° and 40 mm Hg. After cooling to 5°, 250 ml of water is added over a one hour period, maintaining the temperature below 10°, and the suspension is stirred at about 5° for 15 minutes. The solid is filtered off, washed with 200 ml of cyclohexane, and dried at 55° and 40-60 mm for 16 hours to give 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:28]1([CH2:37][C:38](O)=[O:39])[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:28]1[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:48][CH3:49])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:49][O:48][C:30]1[CH:29]=[C:28]([CH:47]=[CH:46][C:31]=1[O:32][CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39])[CH2:27][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (3.06 g), potassium carbonate (2.50 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.43 g, yield: 95%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 127–128° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:9])[CH3:8])=[CH:3][CH:2]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:9][C@H:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH3:8])=[CH:37][CH:38]=2
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(p-tolyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 517 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[N:18][C:17]([N:20]([CH2:28][C:29]4([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:32][CH2:31][CH2:30]4)C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:7][C:4]1[N:3]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[N:18][C:17]([NH:20][CH2:28][C:29]4([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:30][CH2:31][CH2:32]4)=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)nc1
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
To a 20 dram vial was added tert-butyl 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (245 mg, 0.5 mmol) and a 5 mL of a 50% mixture of TFA and CH2Cl2. The reaction was stirred for 15 min, concentrated, and then diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (60% EtOAc/hexanes) to give 91 mg (46%) of 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine. This product was transferred to a 100 mL round bottom flask to which was added hydroxylamine hydrochloride (270 mg), triethylamine (5 mL), and ethanol (20 mL). The reaction mixture was heated to reflux overnight and then concentrated, diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 28 mg of 6-(5-aminopyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine, m/z=351.2 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1nc(-c2cc3c(O)cccc3o2)no1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: Cc1nc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)no1
Yield: 47.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 3-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,2,4-oxadiazole (0.75 g) and (S)-glycidyl nosylate (0.93 g), the title compound (0.45 g) was obtained as white crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6](C2CCCCO2)[C:7]2[C:12]([N:13]=1)=[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[C:9]([Cl:20])[N:8]=2)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O.C(=O)(O)[O-].[Na+]>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[C:9]([Cl:20])[N:8]=2)=[O:4]
Reactant: CNC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 68 h
Yield: 69.9 %

Procedure:
2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine-8-carboxylic acid methylamide (104 mg, 0.27 mmol) was suspended in methanol (6 mL) and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) was added. The mixture was stirred at room temperature for 68 h, then diluted with water and neutralized with aqueous sodium bicarbonate. The solid precipitate was filtered off and dried at 50° C. under vacuum to give 2-chloro-6-morpholin-4-yl-9H-purine-8-carboxylic acid methylamide (56 mg, 70%). LCMS RT=2.43, [M+H]+=297/299
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:33])=[N:10][CH:11]=1)=[O:5].[CH3:35][Mg]I>C1COCC1>[CH2:26]([C:21]1[N:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[N:7][C:6]([C:4](=[O:5])[CH3:35])=[CH:11][N:10]=3)[C@H:13]([CH3:33])[CH2:14]2)=[C:23]([CH3:24])[C:22]=1[CH3:25])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[Mg]I
Reactant: CON(C)C(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methoxy-methyl-amide (example 142, 450 mg, 0.975 mmol) is dissolved in THF (1 mL) and cooled to 0° C. A dropwise addition of methyl magnesium iodide (325 μL, 0.975 mmol) is added dropwise. Reaction is warmed to room temperature and continues to stir for 16 h. Add H2O (1 drop) and concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (60-100% EtOAc/Heptane and 0-8% MeOH/EtOAc) to afford the title compound (350 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[N:26][CH:27]=1
Reactant: O=C(O)c1ccc(-n2cccn2)nc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cccn2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-pyrazol-1-yl-nicotinic acid. MS: 431.4 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18].F[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][C:22]=1[CH3:31].O>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=[C:22]([CH3:31])[C:21]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: CC(C)c1n[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
86 mg (0.624 mmol) of potassium carbonate are added to a solution of 110 mg (0.624 mmol) of 5-hydroxy-3-isopropyl-1H-indazole in 5 ml of DMSO and the mixture is stirred for 1 h. After addition of 106 mg (0.624 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in portions, the mixture is then firstly stirred at room temperature for 2 h, then at 100° C. for 3 h. After cooling to room temperature, the mixture is added to 10 ml of water and the aqueous phase is extracted 3× with ethyl acetate. The combined organic extracts are washed with water and satd NaCl soln, dried over sodium sulphate and concentrated in vacuo. By purification of the resulting residue on silica gel (cyclohexane/ethyl acetate 3:1), 84 mg (41%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.149 g, 0.276 mmol) and 2-aminoethyl-methyl-sulfone (0.3 g, 2.4 mmol), the title compound was obtained as a white solid (75 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.65-7.79 (m, 1H), 7.36-7.53 (m, 3H), 7.22-7.34 (m, 3H), 6.28 (br. s., 1H), 3.60-3.75 (m, 2H), 3.35-3.40 (m, 2H), 3.02 (s, 3H), 1.42 (s, 9H). MS (ESI): 626.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=1)[CH2:8][CH2:7]2.CS(O[CH2:32][CH:33]1[CH2:37][O:36][C:35]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([CH2:38][Br:39])[O:34]1)(=O)=O>CN(C)C=O>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([C:35]2([CH2:38][Br:39])[O:34][CH:33]([CH2:32][O:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[CH2:10][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][CH:16]=3)[CH2:8][CH2:7]4)[CH2:37][O:36]2)=[CH:45][CH:44]=1
Reactant: Oc1ccc2c(c1)CCN(Cc1ccc(-c3ccccc3)cc1)C2
Reactant: CS(=O)(=O)OCC1COC(CBr)(c2ccc(Cl)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc4c(c3)CCN(Cc3ccc(-c5ccccc5)cc3)C4)O2)cc1
Reaction time: 1 h

Procedure:
1.1 g of sodium hydride (50% suspension in oil) are added in portions, with cooling, to a solution of 6.3 g of 6-hydroxy-2-(4-phenylbenzyl)-1,2,3,4-tetrahydroisoquinoline in 100 ml of dry dimethylformamide. The mixture is stirred at 50° for 1 hour and then 7.7 g of (2RS,4SR)-2-(4-chlorophenyl)-2-bromomethyl-1,3-dioxolan-4-ylmethyl methanesulfonate (preparation as in European Offenlegungsschrift No. 0,050,298) are added. The mixture is stirred at 80° C. for 5 hours and cooled, the solvent is removed under oil pump vacuum, and the residue is taken up with a mixture of water and methylene chloride. After washing twice with water and drying over magnesium sulfate, the solution is evaporated in a rotary evaporator, and the residue is chromatographed on silica gel with a mixture of methylene chloride and ethyl acetate in the ratio 3:1. 7.0 g of a highly viscous oil (58% of theory) are obtained.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:22](OCC)[CH3:23].C1(N)CC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:21]1([N:2]2[C:12]3[C:11](=[CH:16][C:15]([F:17])=[C:14]([F:18])[CH:13]=3)[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]2)[CH2:23][CH2:22]1
Reactant: CCOCC
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Agent: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (Example 48a) (75 g, 249 mmol) in a mixture of Ethanol (100 mL)/Diethyl ether (200 mL) was added to cyclopropanamine (34.5 mL, 498 mmol). After 2 h of stirring at rt, LCMS showed complete disappearance of starting material. The reaction mixture was evaporated under reduced pressure, the oily residue was dissolved in N,N-Dimethylformamide (DMF) (250 mL) and potassium carbonate (103 g, 747 mmol) was then added. The reaction mixture was stirred at 100° C. for 2 h, and LCMS showed completion of reaction. Cold water was added to the mixture. The precipitates were collected by filtration and dried to afford ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (71 g, 242 mmol, 97% yield) as a pale yellow solid. LCMS: [M+H]+: 294.1.