Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([SH:4])[CH3:3].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=O>C1CCCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[S:4][CH:2]([CH3:3])[CH2:1][S:5]1
Reactant: O=Cc1ccco1
Reactant: CC(S)CS
Solvent: C1CCCCC1
Product: CC1CSC(c2ccco2)S1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer and magnetic stirring bar and hot plate with magnetic stirring apparatus is placed 0.5 grams paratoluenesulfonic acid, 5 ml cyclohexane and 5.4 grams (0.05 moles) of 1,2-propanedithiol. Over a period of 25 minutes with stirring is added 4.8 grams (0.05 moles) of 2-furaldehyde. The reaction mass is then heated to reflux and refluxed for a period of 8 hours while removing water of reaction. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of aqueous saturated sodium chloride, and dried over anhydrous sodium sulfate. The reaction mass is then filtered and the filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide (Intermediate 13, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)N
Reactant: Brc1cncc2ncc(Br)n12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Nc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 68.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added isopropylamine (1.3 ml, 14.4 mmol). The mixture was heated at 70° C. overnight. The mixture was then cooled to rt, diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 125 mg (yield 68%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2Cl)[CH2:2][CH2:3][CH3:4].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27].Cl.N1C=CC=CC=1>C(OCCO)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2[NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:25]=1[Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(Cl)c(C#N)cnc2cc1OCCOC
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: CCCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1OCCOC
Temperature: 120 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
A mixture of 6-butoxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (184 mg, 0.55 mmol), 2,4-dichloro-5-methoxyaniline (127 mg, 0.66 mmol) and pyridine hydrochloride (76 mg, 0.66 mmol) in 5 mL of 2-ethoxyethanol is heated at 120° C. for 7 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. Diethyl ether is added to the residue and the solids are collected and suspended in saturated aqueous sodium bicarbonate. After stirring for 1 hour the solids are collected by filtration and washed with water. Purification by preparatory thin layer chromatography, eluting with 7% methanol in dichloromethane provides 93 mg of 6-butoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 166-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (5.4 g, 22.5 mmol) in 16 mL of ethanol and potassium cyanide (1.63 g, 25 mmol) in 4 mL of water was heated at 80° C. overnight, then cooled, and the solids were filtered and washed with ethanol to give 3.5 g of 2,5-dichlorophenylacetonitrile as a white powder melting at 89-91° C. The nitrile was suspended in 20 red, of ethanol, and 20 mL of a 25% aqueous NaOH solution was added. The mixture was heated in a CEM Explore™ microwave reactor at 140° C. for 30 minutes, then cooled, poured into ice water and acidified to pH 1 with concentrated HCl to give a precipitate. The precipitate was filtered, washed with water and dried in a vacuum oven at 90° C. for 5 h to give the title compound as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(N2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
A degassed mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.31 mmol), Pd(PPh3)4 (35 mg, 0.031 mmol), tributyl(1-ethoxyvinyl)stannane (221 mg, 0.61 mmol) in dioxane (6 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through a 9:1 SiO2:KF plug and concentrated in vacuo. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=3.58 Min (10 min run, UV254nm). Mass calculated for M+H 828.45, observed LC/MS m/z 828.07 (M+H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH2:4][CH2:3][CH2:2]1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)=O.C([Li])(C)(C)C.[CH3:24][C:25]1(C)[C:29](=O)[CH:28]=[CH:27][C:26]1(C)C>C1COCC1>[CH3:15][C:14]1[C:26]([CH3:27])=[C:25]([CH3:24])[CH:29]([CH3:28])[C:13]=1[C:12]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC1(C)C=CC(=O)C1(C)C
Reactant: [Li]CCCC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3c2NCCC3)=C1C
Temperature: -78 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
1,2,3,4-tetrahydroquinoline (957 mg, 7.185 mmol) was dissolved in THF (10 mL), and the resultant solution was stirred at −78° C. for 30 minutes. Then, n-BuLi (2.87 mL, 7.185 mmol) was added with a syringe in the nitrogen atmosphere. The resultant solution was heated up to the room temperature and stirred sufficiently for 3 hours. The solution was cooled down to −78° C. again, and CO2 gas was added to initiate a reaction. The solution was heated up to the room temperature and stirred to eliminate the remaining CO2 gas. Tert-butyl lithium (BuLi) (5.07 mL, 8.622 mmol) was added at −20° C. After sufficient 2-hour agitation still at −20° C., a 0.33 M solution of CeCl3.2LiCl (26.1 mL, 8.622 mmol) in THF and tetramethyl cyclopentenone (1.182 g, 8.622 mmol) were added in the nitrogen atmosphere. While slowly heated up to the room temperature, the resultant solution was vented, removed of the solvent, and then subjected to extraction with water and ethyl acetate. The organic phase thus formed was separated and removed of the solvent. Then, 8-(2,3,4,5-tetramethyl-1,3-cyclopentadienyl)-1,2,3,4-tetrahydroquinoline was obtained through column chromatography (41% yield).
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:33])[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:33])[CH:15]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:43][C:40]1[CH:41]=[CH:42][C:37]([C:36]([O:35][CH3:34])=[O:45])=[CH:38][CH:39]=1
Reactant: O=C(Cc1cccc(-c2ccc(OC(F)(F)F)cc2)c1)c1ccccc1F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(=O)c2ccccc2F)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Temperature: -78 °C

Procedure:
Sodium t-butoxide (67 mg, 0.70 mmol) was added all at once to a THF solution (4 mL) containing the intermediate from Step B (250 mg, 0.668 mmol) stirred at −78° C. After 2 minutes 4-bromomethyl-benzoic acid methyl ester (161 mg, 0.70 mmol) was added all at once. The reaction solution was allowed to warm to room temperature. After stirring for 1 hour the reaction solution was partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.92-7.90 (m, 2H); 7.79-7.75 (m, 1H); 7.51-7.49 (m, 2H); 7.47-7.32 (m, 4H); 7.30-7.27 (m, 2H); 7.24-7.19 (m, 3H); 7.17-7.15 (m, 1H); 7.05 (dd, J=8.3, 11.3 Hz, 1H); 4.88 (t, J=7.4 Hz, 1H); 3.91 (s, 3H); 3.68 (dd, J=7.1, 13.7 Hz, 1H); 3.17 (dd, J=7.6, 13.7 Hz, 1H). LCMS1 4.40 min. (M+H)− 523
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([CH3:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.ClC1C([N+]([O-])=O)=CC=C(C)C=1C(NC1C=CC=CC=1)=O.O>CCO>[NH2:18][C:5]1[C:6]([CH3:17])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1C(=O)Nc1ccccc1
Agent: Cc1ccc([N+](=O)[O-])c(Cl)c1C(=O)Nc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1c(N)ccc(Cl)c1C(=O)Nc1ccccc1

Procedure:
To a stirred mixture of 6-chloro-2-methyl-3-nitro-N-phenylbenzamide 9 and 2-chloro-6-methyl-3-nitro-N-phenylbenzamide I-9′ (33.6.8 g, 116 mmol, 1.0 eq) in EtOH (400 mL), SnCl22.H2O (105 g, 464 mmol, 4.0 eq) was added and the resulting mixture was stirred at reflux for 3 h. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was poured into water (500 mL) and the mixture was extracted with ethyl acetate (5×500 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% ethyl acetate-petroleum ether) to afford the regio-isomer, 3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10. The remaining mixture of 3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10 and 5-amino-6-chloro-2-methyl-N-phenylbenzamide I-10′ was collected separately. Compound I-10′ was obtained by further column chromatography purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:63][CH2:62]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added, DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.081 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.082 g (77%) of 3-[4-(2-chloro-phenylamino)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 449.17 (M+1)+, 98.46%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (s, 1H), 8.2 (dd, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.5-7.2 (m, 2H), 7.3 (d, 1H), 7.2 (t, 1H), 6.9 (d, 1H), 6.4 (t, 1H), 4.9 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.7-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.9-2.7 (m, 1H), 2.0 (t, 2H), 1.6-1.5 (m, 1H), 1.4-1.3 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][C:26]([N:29]1[C:33]([NH2:34])=[CH:32][C:31]([CH3:35])=[N:30]1)([CH3:28])[CH3:27]>C(O)(=O)C>[CH3:28][C:26]([N:29]1[C:33]2[N:34]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:32]=2[C:31]([CH3:35])=[N:30]1)([CH3:25])[CH3:27]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (327 mg, 1.305 mmol), benzene (8 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (200 mg, 1.305 mmol), and acetic acid (2 mL). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 0.41 g (85%) of product. LCMS E-S (M+H)=368.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 9 H), 2.55 (s, 3 H), 7.11 (d, J=8.84 Hz, 2 H), 7.89 (s, 1 H), 8.16 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][C:34]=1[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][C:34]=1[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:48][CH2:47]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc2nc(CCCC3CCNCC3)cnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cnc4ccccc4n3)CC2)[C@@H](c2ccccc2)C1
Yield: 115.7 %

Procedure:
The title compound was prepared from 50 mg (0.12 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 55 mg (015 mmol) of 4-(3-(quinoxalin-2-yl)propyl)piperidine.2 TFA (from EXAMPLE 73, Step A) using a procedure analogous to that described in EXAMPLE 71, Step A. Flash chromatography using 19:1 v/v CH2Cl2/MeOH afforded 77 mg (100%) of the title compound: 1H NMR (500 MHz) 80.83-3.36(35H), 3.81 (s, 3H), 5.11 (ABq, J=11.9, 2H), 6.89 (d, J=8.7, 2H), 7.16-7.35 (7H), 7.70-7.78 (2H), 8.03-8.10 (2H), 8.73 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2ncccc12
Product: Clc1nccc2ncccc12
Temperature: 0 °C

Procedure:
A solution of 1,6-naphthyridin-5(6H)-one (3.2 g, 21.9 mmol) in phosphoryl trichloride (50 mL) was stirred at 100° C. overnight. The solvent was removed under vacuum. The residue was cooled to 0° C. Sodium hydroxide (saturated aqueous solution) was added to adjust the pH to 9. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 3.3 g of the crude product as a yellow solid. MS (ESI): m/z 165 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4].[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:5]1[N:6]([CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:34]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:35])[CH2:24][CH2:25]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3ccc(OCCC4CCNCC4)cc3c2n1C
Reactant: O=C(Cl)C1CCCC1
Product: CCCCc1nc2c(N)nc3ccc(OCCC4CCN(C(=O)C5CCCC5)CC4)cc3c2n1C

Procedure:
A modification of the method described in Example 15 was used to treat 2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine with cyclopentanecarbonyl chloride. The crude product was purified by column chromatography on silica gel to provide 2-butyl-8-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 147.2-150.1° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.CCN(C(C)C)C(C)C.[S:34]1(=[O:42])(=[O:41])[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.[NH4+].[Cl-:44]>CN(C=O)C>[ClH:44].[CH3:23][C:20]1([CH3:24])[CH2:21][CH2:22][CH:17]([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][NH:40][CH:37]4[CH2:38][CH2:39][S:34](=[O:42])(=[O:41])[CH2:35][CH2:36]4)[C:8]=3[CH:16]=2)[CH2:18][CH2:19]1
Reactant: [Cl-]
Reactant: NC1CCS(=O)(=O)CC1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CNC2CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (200 mg), DIPEA (139 μL), and DMF (3.0 mL) was added tetrahydro-2H-thiopyran-4-amine-1,1-dioxide (97 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column and dissolved in EtOAc, and 4 M HCl/EtOAc (137 μL) was added dropwise. The precipitate was collected by filtration and then dried to obtain N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}tetrahydro-2H-thiopyran-4-amine-1,1-dioxide hydrochloride (165 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[F:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1>>[ClH:1].[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=3)[CH2:30][CH2:29]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Fc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(F)c3)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-di-hydro-2H-indol-2-one and 1-(3-fluorophenyl)-piperazine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C:6]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1
Reactant: [N-]=[N+]=NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol) in 20:1 THF/H2O (3 mL) was added PPh3 (72 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (30 mg, 31%). 1H NMR (400 MHz, CDCl3): δ=2.20-2.51 (m, 2H), 2.51-2.60 (m, 2H), 2.72 (m, 1H), 3.00 (m, 1H), 3.24 (m, 1H), 3.53 (m, 1H), 6.85-6.99 (m, 2H), 7.14 (m, 1H), 7.31-7.50 (m, 8H).