Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl[C:34]1C=C(S(N=C2C3C(=CC=CC=3)C(=O)C(Cl)=C2)(=O)=O)SC=1Cl>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:34])=[CH:29][CH:30]=2)(=[O:22])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)cc1

Procedure:
5.2.42 (N-methyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13g) was prepared according to the procedure for 13d except using 4, 5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N-methylpropanamide( ) which afforded the title compound 21 mg (32%) as a yellow solid, m.p.: ° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:26][N:25]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:11]\2=[CH:10][CH:9]=[CH:8][CH:7]=3)/[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:33][CH:34]=1)[CH3:24]
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH:24][C:30](=[O:32])[CH3:31])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cc(N)ccc4o3)CC2)ccc1OC
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3nc4cc(NC(C)=O)ccc4o3)CC2)ccc1OC
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a solution of N2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-benzooxazole-2,5-diamine (39.8 mg, 0.1 mmol, 1.0 equiv) and acetyl chloride (0.009 mL, 7.9 mg, 0.1 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added diisopropylethylamine (23.4 μL, 25.9 mg, 0.2 mmol, 2.0 equiv) and the mixture stirred at 100° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.1 mg (19%) of the title compound. MS (ESI): 439.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=NC=C([F:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:31])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine (CAS [407-20-5]) instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH2:18]([N:20]([CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC1(C)OCCO1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(CC1(C)OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 54.4 %

Procedure:
4-t-butyl-2,6-dinitro chlorobenzene (2.5 grams; 0.01 mole), 2-(ethylamino)methyl-2-methyl-1,3-dioxolane (2.9 grams; 0.02 mole) and toluene (50 ml) were placed into a glass reaction vessel equipped with a stirrer, oil bath and thermometer and heated to 70° C. with stirrer for 30 hours. Ethanol (50 ml) was added to the cooled mixture and the solid filtered therefrom. The filtrate was evaporated to a volume of approximately 10 ml. It was then chromatographed on silica gel to yield the desired product (2.0 grams). The product was analyzed for C17H25N3O6 :
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH2:35])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:8][CH:7]=1.O1CCCC1.[S:42](Cl)([C:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:50]([N:51]([CH3:53])[CH3:52])[C:49]=2[CH:48]=[CH:47][CH:46]=1)(=[O:44])=[O:43]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH:35][S:42]([C:45]1[C:57]2[C:49](=[C:50]([N:51]([CH3:53])[CH3:52])[CH:54]=[CH:55][CH:56]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:44])=[O:43])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](NS(=O)(=O)c1cccc2c(N(C)C)cccc12)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid methyl ester (0.75 g, Reference Example 30), anhydrous tetrahydrofuran (25 ml), dansyl chloride (0.62 g) and triethylamine (1.0 ml) was placed under an atmosphere of argon and stirred at ambient temperature for 4 hours then heated to reflux for 2 hours. The reaction mixture was cooled then filtered. The filtrate was evaporated and the residue was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (49: 1, v/v to give the title compound (0.89 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2CCc3ccccc3O2)CC1
Reaction time: 16 h
Yield: 74.8 %

Procedure:
First 1.57 g (10 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and then, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.17 g (85.7%) of crude product are obtained and are chromatographed on 110 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.90 g (75.1%) of 1-[2 -(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are thus obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 190°-192°.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([O-:25])=[O:24].[K+]>>[C:1]([O:24][C:23](=[O:25])[CH:22]([NH2:21])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)CC(N)C(=O)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)C(N)CC(C)C
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27 g (70 mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 13.03 g (77 mmol) of potassium 2-amino-4-methylpentanoate. The round bottomed flask is placed in an ice bath and the stearoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-4-methylpentanoic stearic anhydride.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]C=O)=[CH:13][CH:12]=1.C(O)(=O)C>O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:7]2[O:6][C:4](=[O:5])[C:3](=[CH2:8])[CH2:2]2)=[CH:13][CH:12]=1
Reactant: C=C(CBr)C(=O)OC
Reactant: COc1ccc(CCC=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: C=C1CC(CCc2ccc(OC)cc2)OC1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 54.6 %

Procedure:
To a suspension formed from metallic tin (730 mg, 6.15 mmoles), diethyl ether (12.5 ml) and water (3.1 ml) were added 1.10 g (6.15 mmoles) of methyl 2-bromomethyl-2-propenoate and 1.11 g (6.77 mmoles) of 3-(4-methoxyphenyl) propanal, with catalytic quantities of acetic acid. The mixture was kept warm at 50° C. with stirring for 9 hours. At the end of this time it was poured into water (200 ml) and an extraction was performed with diethyl ether (3×100 ml). The result was dried over anhydrous sodium sulphate and vacuum concentrated, giving an oil 780 mg (70% yield) of 5-[2-(4-methoxyphenyl)-ethyl]-3-metylene-dihydrofuran-2-one [(I), R═CH3; R1═H].
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:42]I.O>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]([CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH3:42])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(C)Cc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (247 mg) was dissolved in DMF(2 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 13.56 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (73.5 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound(169 mg) as a white amorphous.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:37][C:38]1[C:46]([O:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][C@H:50]([NH2:54])[CH2:49]2)=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[N:41][NH:42]2>CN(C)C=O>[CH3:3][CH:2]([CH3:4])[C:1]([NH:54][C@H:50]1[CH2:51][CH2:52][CH2:53][C@@H:48]([O:47][C:46]2[C:38]([CH3:37])=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][N:41]=[CH:40]3)[CH2:49]1)=[O:5]
Reactant: CC(C)C(=O)O
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(O[C@@H]2CCC[C@H](NC(=O)C(C)C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Isobutyric acid (36.2 μL, 0.39 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (74.8 mg, 0.39 mmol), hydroxybenzotriazole (52.8 mg, 0.39 mmol) and triethylamine (0.18 ml, 1.28 mmol) were added to a solution of monohydrochloride (100 mg, 0.35 mmol) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example 411 in N,N-dimethylformamide (5 ml), and the resulting mixture was stirred overnight at room temperature. The reaction solution was partitioned by the addition of ethyl acetate, toluene and water, and then extracted twice with ethyl acetate-toluene (1/1). The extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 0/1) to obtain 2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (86.3 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][C:23]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])=[N:22][N:21]=1>>[OH:29][C:25]([C:23]1[O:24][C:20]([CH3:19])=[N:21][N:22]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)c1nnc(C)o1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: Cc1nnc(C(C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)o1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-methyl-1,3,4-oxadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (14 mg, 10%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]1N(C)C.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:6]([CH2:4][CH2:5][C:2]([CH3:13])([CH3:1])[CH:3]=[CH:15][C:14]([OH:17])=[O:16])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C1CC(C)(C)C1N(C)C
Reactant: CC(=O)OC(C)=O
Product: COC(=O)CCC(C)(C)C=CC(=O)O

Procedure:
The process of claim 1 wherein methyl 3,3-dimethyl-2-dimethylaminocyclobutanecarboxylate is reacted with acetic anhydride to produce 6-carbomethoxy-4,4-dimethyl-2-hexenoic acid.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:8]1[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:11])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: Oc1ncccc1OC(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(Br)cc1OC(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
As shown in step 3(a)-iv of Scheme 3(a), 3-(difluoromethoxy)pyridin-2-ol (986 mg; 6.12 mmol) was dissolved in 25 mL of glacial acetic acid and sodium acetate (79 mg; 9.6 mmol) was added. The mixture was cooled in an ice bath and bromine (780 μL; 1.63 g; 10.22 mmol) in 10 mL of glacial acetic acid was added over 10 minutes. The reaction was stirred for 30 minutes at 10-15° C. The volatiles were removed under reduced pressure and the residue was partitioned between brine/saturated sodium carbonate solution and ethyl acetate. After the evolution of gas ceased, the organic and aqueous layers were separated and the aqueous solution extracted three additional times with EtOAc. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The residue was purified twice by silica gel chromatography (first a DCM to 10% MeOH/DCM gradient then 1:1 EtOAc/hexanes) to provide 5-bromo-3-(difluoromethoxy)pyridin-2-ol as a light yellow powder (Compound 2009, 810 mg, 55% yield): ESMS (M+H) 241.9/243.9; 1H NMR (CDCl3) δ 13.2 (br m, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.18 (d, 1H, J=2.1 Hz), 6.92 (t, 1H, J=75 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH2:26][C:27]#[N:28])[CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:29]>>[C:27]([C:26]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:8]([CH3:7])[C:9](=[O:29])[CH:10]=[CH:11]4)[CH:21]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[N:28]
Reactant: Cn1c(=O)ccc2cc(COc3cccc(CC#N)c3)ccc21
Reactant: C1CCOCC1
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C#N)CCOCC4)c3)ccc21
Yield: 61 %

Procedure:
Using the procedure described in the third paragraph of the portion of Example 2 which is concerned with the preparation of 4-ethoxycarbonyl-4-(3-hydroxypheny])tetrahydropyran, 3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenylacetonitrile was reacted with bis-2-chloroethyl ether to give 4-cyano-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 61% yield, m.p. 149°-150° C. (recrystallised from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[CH:8]3[O:9][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[OH:9][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:8]1[N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]1[CH3:15]
Reactant: FC(F)(F)c1ccc2c(c1)CC1OC21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Temperature: 95 °C

Procedure:
A mixture of 4-(trifluoromethyl)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (1.2 g, 6.0 mmol) and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.4 g, 7.2 mol) in ethanol (20 mL) was refluxed overnight. Another gram of tert-butyl (3S)-3-methylpiperazine-1-carboxylate was added. The mixture was transferred into a sealed flask and heated to 95° C. for 2 days. The solvent was concentrated and the residue was purified by flash chromatography eluting with 25% EtOAc/hexane, followed by 5% MeOH/EtOAc+0.5% concentrated NH4OH. Two isomers were isolated. Isomer 1 (fast moving isomer): 0.45 g; MS calculated for the C20H27F3N2O3 (M+H)+401; found 401.1. Isomer 2 (slow moving isomer): 0.38 g; MS found 401.1.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1C=CC=C[CH:5]=1.[C:11]([C:16]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([CH3:22])(C)[CH2:19][CH2:18][NH:17]1)([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:26]([O:25][C:23]([C:16]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:20]([C:22]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:19][CH2:18][NH:17]1)=[O:24])[CH3:27]
Reactant: O=CC=Cc1ccccc1
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Product: CCOC(=O)C1(C(=O)OCC)NCCC1c1ccccc1

Procedure:
Diethyl-3-phenylpyrrolidine-2,2-dicarboxylate was prepared from cinnamaldehyde (1.22 mL, 9.70 mmol) essentially according to the procedure described in U.S. Pat. No. 4,060,603 for the preparation of 2,2-dicarboethoxy-3,3-dimethyl-pyrrolidine. The resulting yellow oil was used in the next step without purification. LCMS RT=1.26 min. LCMS (M+H)=292.1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O>>[CH:1]1([N:6]2[C:10]3=[N:11][C:24]([C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: Cc1cccc(C=O)n1
Agent: CS(=O)(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(C)n3)nc(=O)c1-2
Yield: 53.3 %

Procedure:
1-Cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 6-methyl-2-pyridinecarboxaldehyde (2.2 g, 18.0 mmol), methanesulfonic acid (0.5 ml) and xylenes (80 ml) were combined and heated to reflux for 24 hours. The solvents were removed in vacuo, ethanol was added and the solvents were removed in vacuo. The residue was partitioned between 10% K2CO3 and chloroform, the organic layer was separated and the aqueous layer was extracted with chloroform (3×200 ml). The combined organic layers were concentrated in vacuo, redissolved in dichloromethane and combined with silica gel (40 g). The slurry was air dried for 3 hours, and placed on a silica gel column (150 g). Elution with ether and concentration of the solvent in vacuo and drying the residue at 40° C. in high vacuum for 6 hours afforded 1.55 g (53%) of 1-cyclopentyl-3-ethyl-6-(6-methyl-2-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:14])=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:13][C:6]1[CH:5]=[C:4]([F:14])[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN)c(F)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)c(F)cc1Cl
Yield: 99.8 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate (180 mg, 0.83 mmol), DIPEA (321 mg, 2.49 mmol) and pivaloyl chloride (120 mg, 1.0 mmol) in CH2Cl2 (5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.16 (t, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.58-7.54 (d, J=10.2 Hz, 1H), 4.26-4.24 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 1.11 (s, 9H).