Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[OH:28])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(O)c1
Yield: 58 %

Procedure:
A mixture of 369 mg (0.77 mmole) of N-ethoxycarbonyl-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinone and 414 mg of 5% palladium on carbon (50% wet) in 5 ml ethanol was stirred under 1 atmosphere of hydrogen at 25° C. until the hydrogen uptake is complete (approximately 3 hours). The reaction is filtered through a filter aid, washing with ethanol and the filtrate evaporated in vacuo. The residual crude oil is purified via column chromatography on 22 g of silica gel eluting in 4 ml fractions with 15% ethyl ether in dichloromethane to yield (fractions 28-42) 174 mg (57%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:58])([CH3:59])[CH3:60])=[CH:54][CH:55]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (238 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-1-naphthamide (252 mg, 42%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1ccccc1
Product: c1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenol to give (1-phenoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 303(MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.056 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.5 mL of N,N-dimethylacetamide and 0.018 mL (0.0003 mole) of iodomethane was added 0.012 g (0.0003 mole) of 60% sodium hydride in oil at 0 degrees. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.049 g of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1) as an yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:15]O)[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[ClH:21].[Cl:21][CH2:15][C:9]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]2[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=1
Reactant: Cc1nc(N)c2nc(CO)n(CC(C)C)c2c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(CCl)n(CC(C)C)c2c1C
Product: Cl
Yield: 64.3 %

Procedure:
A solution of (4-amino-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol (1.95 g, 7.85 mmol) and thionyl chloride (1.72 mL, 23.6 mmol) in chloroform (80 mL) was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue triturated with chloroform to give 1.53 g of 2-(chloromethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride as an off-white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1.O>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CCCN(CCCCN)c1ccccn1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCCN(CCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (0.9 g) and 2-nitroamino-5-pyrid-4-ylmethylpyrimid-4-one (0.72 g) were heated together under reflux in pyridine (2.5 ml) for 21 hr. After stripping the residue was taken up in water, basified, and extracted with ether. The aqueous was acidified (pH 6.5), extracted with dichloromethane and stripped to give an oil which was crystallized from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-pyrid-4-ylmethylpyrimid-4-one 1.2 H2O; 0.45 g (38%) m.p. 58°-60° C.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:25]
Reactant: O=C(CCCCSc1ccccc1)N1CCc2occc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCCSc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.250 g (0.793 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-5-phenylthiopentan-1-one in 20 ml of acetic acid, 0.107 ml (1.19 mmol) of 50% aqueous dimethylamine and 0.097 ml (1.19 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 45 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])=[CH:3][CH:2]=1.[N:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:40])[F:41])[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-biphenyl-4-yl-ethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.2% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 7.98, 7.76, 7.64, 7.60-7.52, 7.44, 7.38-7.30, 7.00, 4.06, 3.88, 3.82-3.68, 3.36, 2.98.
Reaction SMILES: F[C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1.BrC1C=C(S(C)(=O)=O)C=CC=1OC[CH:49]1[CH2:51][CH2:50]1>>[CH:49]1([C:2]2[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6]([C:20]3[CH:25]=[C:24]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH:7]=2)[CH2:51][CH2:50]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(C3CC3)c(=O)n(C)c2)c1

Procedure:
The title compound was prepared in a manner similar to Example 119, substituting 3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one and 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.33-0.41 (m, 2H) 0.55-0.61 (m, 2H) 0.63-0.69 (m, 2H) 0.83-0.91 (m, 2H) 1.07-1.14 (m, 3H) 1.19-1.25 (m, 1H) 2.01-2.12 (m, 1H) 3.23-3.30 (m, 2H) 3.52 (s, 3H) 3.92-4.00 (m, 2H) 7.22-7.29 (m, 2H) 7.70-7.80 (m, 3H). LCMS (M+H)+=388.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.O.O.[Sn](Cl)Cl>C(O)C>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:16])[C:7](=[O:15])[NH:8]2)=[C:3]([C:17]#[N:18])[C:2]=1[Cl:1]
Reactant: N#Cc1c(Cl)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c(Cl)c(N)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-5-cyano-7-nitroquinoxaline-2(1H),3(4H)-dione (0.100 g, 0.38 mmol, as prepared above) and tin (II) chloride dihydrate (0.508 g, 2.25 mmol, Aldrich) in ethanol (4.0 mL) was refluxed for 24 h. The resulting suspension was then cooled to room temperature and the yellow solid was filtered, washed with ethanol (2.0 mL), and dried under vacuum to obtain 0.078 g (88%) of 7-amino-6-chloro-5-cyanoquinoxaline-2(1H),3(4H)-dione as a yellow powder; 1H NMR (DMSO-d6): δ 5.762 (br s, 2H), 6.818 (s, 1H), 11.69 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[CH3:13][C:14]1[CH2:15][S:16](=[O:36])[C@@H:17]2[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:35])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21].[Br:37]N1C(=O)CCC1=O>ClC1C=CC=CC=1Cl>[Br:37][CH2:13][C:14]1[CH2:15][S:16](=[O:36])[C@@H:17]2[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:35])[N:18]2[C:19]=1[C:20]([O:22][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: Clc1ccccc1Cl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 0.25 h
Yield: 45 %

Procedure:
0.3 ml of N-methyl-N-trimethylsilyltrifluoroacetamide (1.6 mmoles) was added at room temperature to a suspension of 354 mg (1.02 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 40 ml of o-dichlorobenzene and after stirring for 15 minutes, 20 ml of o-dichlorobenzene were added thereto. Bromination was carried out as described in Example 37 using 310 mg (1.74 mmoles) of N-bromosuccinimide as the brominating agent and irradiation was continued for 80 minutes to obtain trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in a yield of 45%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[CH2:25][CH:24]([CH2:28][N:29]2[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30]2)[CH2:23]1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:34]([C:32]1[CH:31]=[N:30][N:29]([CH2:28][CH:24]2[CH2:25][C:26](=[O:27])[N:22]([C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[F:14])[CH2:23]2)[CH:33]=1)=[O:35]
Reactant: O=C(O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(CC3CC(=O)N(c4ccc(F)cc4F)C3)c2)c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
A mixture of 5,6-Diamino-3-propyl-1H-pyrimidine-2,4-dione (0.12 g, 0.67 mmol) and 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (0.18 g, 0.56 mmol) in methanol (6 ml) was cooled to 0° C. and added EDCI.HCl (0.15 g, 0.78 mmol) and stirred at 25° C. for 20 hours. Solvents were removed under reduced pressure and to this reaction mixture water (10 ml) was added. Solid obtained was filtered off and washed with cold water (20 ml) followed by diethyl ether (25 ml). It was then dried and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 6% methanol in DCM as an eluent to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.165 g, 60%) as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH: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][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, 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 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. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether using 0.18 equivalent of water of crystallisation and melts at 140°-143°.
Reaction SMILES: [CH3:1]I.[P:3]([O:10]CC)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]>>[CH3:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCOP(OCC)OCC
Product: CCOP(C)(=O)OCC
Temperature: -10 °C

Procedure:
188 g (1.32 mol) of methyl iodide are poured under nitrogen into a dry three-necked flask surmounted by an alcohol condenser (-10° C.), and then heated to the refluxing temperature. 168 g (1.02 mol) of triethyl phosphite are then added dropwise. The reaction is exothermic, and the temperature rises in the course of one hour to 73° C. The temperature of the mixture is maintained for one hour at between 70° and 75° C., and the solution is then cooled and concentrated in a rotary evaporator. The diethyl methylphosphonate is distilled under nitrogen, under reduced pressure.
Reaction SMILES: [C:1]1([C:7]2([S:13][CH2:14][C:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:38].[OH2:48]>ClCCl.[Cl-].[Na+].O>[C:1]1([C:7]2([S:13]([CH2:14][C:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=3)=[O:17])(=[O:38])=[O:48])[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(O)(CSC1(c2ccccc2)C=CC=CC1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)C1(c2ccccc2)C=CC=CC1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-phenylphenylthio)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (85 mg, 0.21 mmol) in dichloromethane (0.3 mL) at −78° C. was added 30% hydrogen peroxide (0.036 mL, 1.26 mmol) followed by the slow addition of trifluoroacetic anhydride (0.151 mL, 1.07 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 41 mg of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C=O)C.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.01 g, 2.93 mmol) in DMF (10 mL) was added sodium hydride (0.21 g, 5.25 mmol of 60% dispersion on mineral oil). It was stirred for 50 minutes at room temperature then chilled in an ice bath. Ethyl bromoacetate (0.48 mL, 4.3 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with diethyl ether. The ethereal extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 5-6% tert-butyl methyl ether in hexane as an eluant. The title compound was obtained as a yellow gum (0.749 g, 59%); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 7.9-8.1 (m, 3H), 7.8-7.9 (m, 1H, 7.7-7.8 (m, 1H), 7.3-7.5 (m, 4H), 4.95 (s, 2H), 4.2 (q, 2H, J=7.2 Hz), 2.7 (t, 2H, J=7.6 Hz), 1.45-1.65 (m, 2H), 1.0-1.3 (m, 5H), and 0.7 ppm (t, 3H, J=7.6 Hz).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[C:19]([Cl:21])[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl>C(O)C.O>[Cl:21][C:19]1[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=2)=[N:17][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]2[NH:8][N:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:10]=2)=[O:12])[CH3:31])[CH:20]=1
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 51 %

Procedure:
Into a 0° C. solution containing sodium tetrahydroborate (0.022 g, 0.580 mmol) dissolved in ethanol (1 ml), (S)-3-acetyl-N-(1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (0.125 g, 0.290 mmol) of Example 224 dissolved in 2 ml of ethanol was added slowly. The mixture was stirred at 0° C. for a few minutes after which the mixture was allowed to warm to RT and the stirring was continued for 4.5 h. A few drops of water was added slowly. The pH was adjusted below 4 with 2 M HCl. The solvent was evaporated and the residue extracted with DCM/water. Organic phase was isolated with phase separator and evaporated. The product was purified by recrystallization from ethanol. Yield 51.0%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.38 (d, 3H), 4.23-4.37 (m, 2H), 4.40-4.50 (m, 1H), 4.75-4.83 (m, 1H), 5.40 (d, 1H), 6.40 (s, 1H), 8.00 (dd, 1H), 8.04 (dd, 1H), 8.05-8.14 (m, 3H), 13.03 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].C(=O)([O-])[O-].[K+].[K+].CI.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: O
Product: Cc1cccc(C)c1CO
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (10 g, 66.5 mmol) and potassium carbonate (9.18 g, 66.5 mmol) in dimethylfonnamide (67 ml), was added methyl iodide (8.28 ml, 133.16 mmol) in an ice bath, and the mixture was stirred for 16 hours. To the reaction mixture was added toluene and water, and the organic layer was washed with 3% K2CO3, 1N HCl, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was redissolved in dry THF (135 ml), added to LiAIH4 (3.7 g, 99.8 mmol), and stirred for 4 hours in an ice bath. To the reaction mixture was added 1N HCl slowly followed by ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The oily residue was used without further purification.