Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21](O)=[O:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[O:30]([NH2:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:31][O:30][NH:32][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:22]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Reactant: CON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NOC)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (65 mg) was treated with methoxylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (21 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][C@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][N:22]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CC(NC(=O)OC(C)(C)C)CN(c2cc(C(=O)O)c(Cl)nn2)C1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 3,6-Dichloro-pyridazine-4-carboxylic acid (201) (400 mg, 2 mmol) and (3R,5S)-3,5-bis-tert butoxy carbonyl amino piperdine (4) (1.3 g, 4 mmol) in 14 ml DMF containing iPr2NEt (718 ∥l, 4 mmol) was heated at 100° C. for 25.6 h with shaking. The solvent was removed under reduced pressure. After HPLC purification, compound 207 (483 mg, 51.1%) was obtained as a solid. LC-MS (ESI): m/e=472.3 [M+1]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:16]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:13]([O-:15])=[O:14])[N:4]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2nc(CBr)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2nc(CN3CCOCC3)ccc12

Procedure:
460 mg (1.72 mmol) of 2-bromomethyl-5-nitroquinoline and 0.54 ml (6.2 mmol) of morpholine are dissolved in 150 ml of toluene. After 1.07 g (7.74 mmol) of potassium carbonate is added, the reaction mixture is allowed to reflux for 2 hours. Potassium carbonate is filtered off, and the filtrate is concentrated by evaporation. After purification on silica gel with hexane-ethyl acetate (0–100%), 190 mg (40% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)[CH2:2][CH3:3].S(Cl)([Cl:24])(=O)=O>O1CCCC1>[CH2:1]([C:4]1[C:19]([OH:20])=[C:18]([Cl:24])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:12][N:13]=[N:14][N:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1c(O)cccc1OCCCCc1nnn[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1c(OCCCCc2nnn[nH]2)ccc(Cl)c1O
Reaction time: 1 h

Procedure:
A solution of 1.38 g. of 5-[4-(2-propyl-3-hydroxyphenoxy)butyl]-tetrazole in 25 ml. of tetrahydrofuran was cooled to -10° C. by means of an external alcohol-ice bath. One millimole of sulfuryl chloride was slowly added and the reaction mixture was stirred for one hour. The mixture was evaporated under reduced pressure and the residue was triturated with diethyl ether. The ether was evaporated and the residue was purified by reverse phase high pressure liquid chromatography. The appropriate fractions provided 42 mg. of the desired title product plus 92 mg. of the 2-propyl-3-hydroxy-6-chlorophenoxy isomer and a small amount of the 2-propyl-3-hydroxy-4,6-dichlorophenoxy compound.
Reaction SMILES: [N:1](C1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1)=[N+:2]=[N-].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:56])=[C:36]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[Cl:54])=[CH:42][C:41]=2[Cl:55])=[O:39])[CH:37]=1>>[N:31]([C:32]1[CH:33]=[CH:34][C:35]([CH3:56])=[C:36]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[Cl:54])=[CH:42][C:41]=2[Cl:55])=[O:39])[CH:37]=1)=[N+:1]=[N-:2]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 421 (0.21 mmol). The crude product was used without any further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)C>O>[CH:22]1([NH:27][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC3CCCC3)cc2c1=O
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 140 mg (0.44 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 0.17 ml (1.76 mmol) of cyclopentylamine and 3 ml of ethanol is heated at 150° C. in a closed vial in a microwave reactor for 5 minutes. After cooling to room temperature, water is added and the resulting suspension is filtered. Conc. aqueous hydrochloric acid is added to the filtrate until a pH value of 2-3 is reached and the formed suspension is filtered. The residue is crystallized from ether-hexane to yield 52 mg (31%) of the title compound as red crystals, m.p. 146-155° C.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>C(OCC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:17][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: OCc1cccc(Cl)c1
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(CCC(=O)OCc2cccc(Cl)c2)N1
Temperature: 100 °C

Procedure:
Two hundred and eighty eight milligrams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 600 mg of m-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 40 hours. The mixture is cooled and is dissolved in 50 ml of anhydrous diethylether. The filtrate is cooled to induce crystallization and the resulting crystals are isolated by filtration. Recrystallization from toluene-petroleum ether yields 5-oxo-2-pyrrolidinepropanic acid m-chlorobenzyl ester with a melting point of 90°-91° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([CH3:50])[CH:36]=[CH:35][C:34]([N:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)([C:41]5[CH:40]=[CH:39][C:38]6[N:37]([C:34]7[CH:33]=[CH:32][C:31]([CH3:50])=[CH:36][CH:35]=7)[C:49]7[C:44]([C:43]=6[CH:42]=5)=[CH:45][CH:46]=[CH:47][CH:48]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccc(-n2c3ccccc3c3cc(C4(c5ccccc5)c5ccccc5-c5nc6ccccc6c(-c6ccccc6)c54)ccc32)cc1
Yield: 83.4 %

Procedure:
Referring to the reaction formula above, 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 1.00 mmol) and 9-(p-tolyl)-9H-carbazole (291 mg, 1.20 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 286 of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 8 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 521 mg of 10,11-diphenyl-11-(9-(p-tolyl)-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 83.4%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(F)ccc21
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 50 (286 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 390 mg (98%) of white solids. M.P. 286° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.62 (m, 4H), 3.92 (m, 4H), 7.16 (dd, J=3.5, 5.0, 1H), 7.50 (d, J=3.2 Hz, 1H), 7.63-7.68 (m, 3H), 7.80 (d, J=4.8 Hz, 1H). EIMS m/z 397 (M+1). Anal. (C20H17FN4O2S) C,H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>CS(C)=O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:11]=[CH:10][C:9]([N:15]2[CH2:16][CH2:17][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[N:8][CH:6]=1)=[O:22]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)nc1
Temperature: 85 °C

Procedure:
To a solution of methyl 6-chloronicontinate (200 mg, 1.16 mmol) in DMSO/PhMe (2 mL of a 1:1 solution) was added t-butyl-2,8-diazaspiro[4.5]decane-2-carboxylate (700 mg, 2.91 mmol). The reaction mixture was heated at 85° C. for 6 hours and then diluted with EtOAc (10 mL). The organic layer was washed with NaHCO3 (1×5 mL) and brine (1×5 mL), dried over Na2SO4, and then concentrated. The crude residue was purified by reverse-phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) to give t-butyl 8-[5-(methoxycarbonyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate: MS (ESI+): cal'd [M+H]+ 376.2, obs'd 376.2. This intermediate was then treated with TFA (3 mL) in CH2Cl2 (6 mL). The reaction mixture was concentrated after 30 minutes of stirring at room temperature and the crude residue was purified by reverse-phase flash chromatography (10-75% MeCN/H2O with 0.05% TFA) to give the methyl 6-(2,8-diazaspiro[4.5]dec-8-yl)nicotinate: MS (ESI+): cal'd [M+H]+ 276.2, obs'd 276.2.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21].Cl>>[C:20]([O:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(Oc2ccc(O)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Oc2cccc(C(=O)O)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
An amount of 3-(4'-hydroxyphenoxy)benzoic acid (9.772 g, 42.45 millimoles (mmoles)) was dissolved in 6M NaOH (18 ml, 108 mmoles) and cooled in an ice bath. Acetic anhydride (8.0 ml, 11.1 g, 109 mmoles) was added cautiously to the basic solution at such a rate as to maintain 0° to 5° C. and then stirred vigorously for an additional 15 minutes (min) at 0° C. The reaction mixture was then allowed to warm to room temperature over 1 hour. The aqueous solution was acidified with 6M HCl (18 ml, 108 mmoles) and extracted with 75 ml of ethyl acetate. The organic solution was washed three times with a 50 ml saturated solution of NaCl, dried with MgSO4, filtered, and solvent evaporated. The crude product was taken up in methanol, treated with activated carbon, filtered through a celite pad, and evaporated. Recrystallization of the product gave 9.83 g of 3-(4'-acetoxyphenoxy)benzoic acid as an off-white powder with a m.p. 141° C. to 143° C.
Reaction SMILES: [CH:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:1]1([S:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:13][CH:14]=2)=[O:44])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSC4CCCCC4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)C4CCCCC4)cc2)CCO3)cc1
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
To a solution of N-(4-(cyclohexylthiomethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.19g) in dichloromethane (5ml) was added 70% m-chloroperbenzoic acid (0.097g) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/dichloromethane) to give crude crystals, which were recrystallized from ethanol to give N-(4-(cyclohexylsulfinylmethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 106) (0.048g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:46])[C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[N:33][CH:32]=[C:31]([CH:30]([F:46])[F:29])[CH:36]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cncc(C(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 3.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.18 mmol) was treated with 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (237 mg, 0.93 mmol, prepared according to WO2012/087237), sodium carbonate (2M, 700 μl, 1.40 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.02 mmol) according to the method described in Example 3 to give 3 mg (3% yield) of the title compound. Purity 98%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH2:3]1.[CH3:13]O>S(=O)(=O)(O)O>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3]1
Reactant: O=C(O)CCC1=CCC(=O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC1C=CC(=O)CC1

Procedure:
A solution of 3.5 g of 4-oxocyclohex-1-enepropionic acid in 16.5 ml of methanol and 0.9 ml of concentrated sulfuric acid was refluxed for 30 minutes. The mixture was cooled and the solvent was evaporated under reduced pressure. The resulting residue was partitioned between 50 ml of 5% aqueous sodium bicarbonate and 100 ml of ether. The separated aqueous layer was washed twice with 100-ml portions of ether and the washings were combined with the original organic layer and dried over magnesium sulfate. The solvent was evaporated to give a crude product which was found to be a 1:1 mixture of double bond isomers by NMR analysis. Flash chromatography of this crude product (silica gel, 3:7 ethyl acetate-hexane) separated the compounds and gave methyl 4-oxocyclohex-2-enepropionate as a clear oil. 1H NMR (CDCl3) δ 3.60 (s, 3H); 5.70-6.00 (dd, 1H); 6.60-6.95 (d of m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH:16]([S:19](Cl)(=[O:21])=[O:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Clc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 3.3 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in chloroform and reacted with 2.4 g. of isopropanesulfonyl chloride in the presence of 2.3 g. of potassium carbonate for several days at ambient temperature. The reaction mixture was worked up as described in Example 4, and the oily product was dissolved in chloroform and purified over silica gel, eluting with chloroform, to obtain 0.6 g. of the desired product, the elemental analysis which was as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[CH:30]=1>>[Cl:24][C:25]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:31](=[O:35])[CH:30]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2Cl)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 44.9 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (110 mg, 0.411 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (105 mg, 45%) as a yellow foam: ESI MS m/z 568 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[Cl:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.10 g, 10.0 mmol) in 25 mL of DCM was added sulfuryl chloride (1.05 ml, 13.0 mmol) slowly under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was treated with DCM (30 mL), washed with ice H2O, saturated aqueous NaHCO3 and brine, and dried with Na2SO4. Removal of the solvent under reduced pressure yielded the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.40 (q, J=7.2 Hz, 2H), 4.07 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.40 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C11H17ClN2O2: 245.1 (M+H), Measured: 245.1.
Reaction SMILES: C([BH3-])#N.[Na+].C1(N2[C:15]([CH:16]3CCC[O:17]3)=[C:14]([C:21]3ON=[C:23]([C:26]4C=CC(C=O)=CC=4)[N:22]=3)C=N2)CCCCC1.C(O)(=[O:36])C>CO>[NH:22]1[CH2:21][CH2:14][CH:15]([C:16]([OH:17])=[O:36])[CH2:26][CH2:23]1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(C4CCCCC4)c3C3CCCO3)n2)cc1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1CCNCC1
Yield: 200 %

Procedure:
Sodium cyanoborohydride (17.3 mg; 0.275 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(tetrahydrofuran-2-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (99 mg; 0.25 mmol), obtained from step 2, and isonipecotic acid (64.6 mg; 0.50 mmol) in methanol (3 mL) and acetic acid (45 μL; 0.75 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material purified by reverse phase preparative HPLC to give Example 125 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.20 (1 H, s), 8.04 (2 H, d, J=8.0 Hz), 7.54 (2 H, d, J=8.0 Hz), 5.72 (1 H, dd, J=9.5, 6.9 Hz), 4.47 (1 H, d, J=8.2 Hz), 4.16 (1 H, q, J=7.5 Hz), 3.97 (1 H, q, J=7.5 Hz), 3.57 (2 H, s), 2.79 (2 H, d, J=10.9 Hz), 2.55-2.50 (1 H, m), 2.26-2.13 (3 H, m), 2.11-1.78 (11 H, m), 1.72 (1 H, d, J=12.5 Hz), 1.65-1.52 (2 H, m), 1.50-1.35 (2 H, m), 1.35 (1 H, m). LC/MS: 506 (M+H)+. HPLC (Method B) Rt 2.77 min (Purity: 99.2%).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C(C2C=CC=CC=2)=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C=CC=CC=1.[CH3:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([Cl:32])=[O:31].Cl>C1COCC1>[ClH:32].[NH2:14][CH:15]([C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[CH3:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1ccccc1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Under nitrogen, 4.2 g (0.038 mol) of potassium tert-butoxide were suspended in THF. The mixture was cooled to −78° C., and 10.0 g (0.037 mol) of ethyl N-(diphenylmethylene)glycinate, dissolved in THF, were added dropwise. After 40 min at −78° C., the solution was transferred into a cooled dropping funnel (−78° C.) and added dropwise to a solution, cooled to −78° C., of 2-methylbenzoyl chloride in THF. After 1 h of stirring at −78° C., the reaction mixture was allowed to warm to 0° C. over a period of 2 h. The mixture was hydrolyzed using 10% strength hydrochloric acid, and stirring was continued. The solvents were removed and the residue was taken up in water and washed with MTBE. The aqueous phase was concentrated, methanol was added to the residue and the mixture was filtered. Concentration of the filtrate gave 6.2 g of the title compound as a colorless oil.