Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54](O)=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49].CCN(C(C)C)C(C)C>CN(C=O)C>[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)[CH3:5])=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49]
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCN)CC1
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-phenyl-amine (200.0 mg, 0.57 mmol), EDCI (120.0 mg, 0.62 mmol) and HOBT (84.3 mg, 0.62 mmol) were combined in DMF (25 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (109.3 mg, 0.62 mmol) followed by DIPEA (119.0 μL, 0.68 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (97:2:1, CH2Cl2/MeOH/NH4OH) afforded 4-cyano-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-benzamide as an off-white foam (209.0 mg, 72%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz), 1.04 (m, 1H), 1.30 (m, 1H), 1.59 (m, 1H), 1.64 (s, 2H), 1.76 (m, 1H), 1.86 (m, 2H), 2.21 (t, 1H, J=11 Hz), 2.32 (s, 6H), 2.55 (t, 1H, J=11 Hz), 2.78 (m, 3H), 2.87 (s, 2H), 2.95 (s, 3H), 3.35 (m, 1H), 3.64 (m, 1H), 3.78 (sext, 1H, J=6 Hz), 4.07 (s, 2H), 6.59 (d, 2H, J=9 Hz), 6.73 (t, 1H, J=8 Hz), 7.14 (m, 3H), 7.50 (m, 1H), 8.01 (s, 1H), 8.28 (s, 1H), 8.35 (d, 1H, J=5 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:27][C:28]2[N:32]=[CH:31][NH:30][N:29]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: Nc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNc1nc[nH]n1
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (62.3 mg, 0.149 mmol) and 3-amino-1H-1,2,4-triazole (38.8 mg, 0.461 mmol) in DMA (4 mL) was added NaH (58.8 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a white solid (30.2 mg, 48%). LCMS m/z (%)=422 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][C:10]([CH3:18])=[N:11][C:12]=1[NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]1[N:13]([C@H:14]([CH3:17])[CH2:15][OH:16])[C:12]2[C:7]([N:6]=1)=[C:8]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[N:9]=[C:10]([CH3:18])[N:11]=2
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(N[C@H](C)CO)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n([C@H](C)CO)c2n1
Temperature: 160 °C

Procedure:
Combine 2-chloro-N-[4-chloro-6-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]-2-methyl-pyrimidin-5-yl]benzamide (13.0 g), IPA (11 mL), of N-methylpiperizine (7.1 mL) and diisopropylethylamine (7.0 mL) in a 300 mL Parr autoclave with mechanical stirrer. Seal the reaction vessel and heat to 160° C. for 24 h. Evaporate all volatile materials, dissolve in dichloromethane (100 mL) to give a dark solution. Wash with water (2×50 mL), dry using a hydrophobic frit, and evaporate all the solvent under reduced pressure. Take the resulting solid and dissolve in acetonitrile (85 mL) and stir. After 1.5 h collect the solids by filtration and air dry, before dying under vacuum to provide the title compound (10.73 g). Determine optical purity by chiral SFC to show a single enantiomer. ES/MS m/z 401.2 (M+1). Chiral HPLC conditions: Diacel AD-H, 10% IPA, 0.2% isopropylamine, 89.8% supercritical carbon dioxide, UV (220 nm), TR=4.22 min, 100% ee.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]=O)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:18][C:19](OC(C)=O)=[O:20]>>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:19](=[O:20])[CH:18]=[CH:9][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2ccc(=O)oc2n1
Temperature: 120 °C
Yield: 30 %

Procedure:
To 6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbaldehyde (318 mg, 2.3 mmol) in Ac2O (3 mL) was added Et3N (1 mL). The reaction was heated at 120° C. for 18 hours. The reaction was concentrated and the resulting material was dissolved in MeOH and loaded onto silica gel and evaporated. Purification by column chromatography (silica gel) using a hexanes/ethyl acetate gradient (0-100% EtOAc) provided the desired product as a solid (80 mg, 30%). LCMS (ES+) m/z 162 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])=O)(C)(C)C.[ClH:19].CCOCC>O1CCOCC1>[ClH:19].[NH2:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C1CC1(CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (2.05 g, 8.0 mmol) in dry 1,4-dioxane (40 mL) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and ether was added (100 mL). The white solid was collected and dried to give 1-aminomethyl-2-isopropyl-cyclopropanecarboxylic acid hydrochloride (1.35 g, 88%): mp: 245–246° C.; 1H NMR (300 MHz, D2O) δ 0.94 (d, J=6.5 Hz, 3H), 0.96 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 1.23–1.31 (m, 1H), 1.49–1.59 (m, 2H), 2.85 (d, J=13.7 Hz, 1H), 3.83 (d, J=13.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ 22.3, 23.9, 27.8, 30.8, 39.6, 41.7, 179.6; MS (APCI) m/z 158 [M+H]+. Anal. Calcd. For C8H15NO2—HCl: C, 49.61; H, 8.33; N, 7.23; Cl, 18.31. Found: C, 49.76; H, 8.44; N, 7.11; Cl, 18.48.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[C:13]1([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(=S)=S>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([C:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.6 g. (0.054 mol.) of 2-phenylbenzofuran in 40 ml. of carbon disulfide is added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture is warmed to ambient temperature and stirred for 2 hours. The mixture is then poured onto 100 ml. of ice-water and stirred for 1 hour. The solvent is removed, and the product extracted into chloroform and the extracts are washed with water, dried (Na2SO4) and concentrated under reduced pressure to give 3-(3-methyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [C:1]([CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1([Cl:13])[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#CC1CC2C3CC4C2C4C13
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1(Cl)CC2C3CC4C2C4C31
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 8-cyanotetracyclo-[4,3,0,02,4,03,7 ]nonane (87 g.) in carbon tetrachloride (600 ml.) was added phosphorus pentachloride (168 g.). The mixture was heated under reflux for 60 hours, cooled and poured into a mixture of crushed ice and water (1.1). The mixture was stirred for 30 minutes and the organic layer separated. This was washed with a 10% w/v aqueous solution of sodium carbonate (200 ml.), saturated brine (100 ml.) and then dried over anhydrous potassium carbonate. The filtrate was then evaporated in vacuo to remove solvent and then distilled in vacuo to give 8-cyano-8-chlorotetracyclo[4,3,0,02,4,03,7 ]nonane, b.p. 136°-140° C./20 mm., in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:39])[NH:34][C:35](=[S:38])[NH:36][CH:37]=2)=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>ClCCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][S:38][C:35]3[NH:36][CH:37]=[C:32]([CH2:31][C:28]4[CH:29]=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[C:33](=[O:39])[N:34]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 21.6 %

Procedure:
The same procedure as E63 from 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (200 mg, 0.578 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (174 mg, 0.693 mmol) and DIPEA (0.303 mL, 1.733 mmol) in DCE (3.0 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (70 mg, 21.64% yield). LCMS: rt=3.44 min, [M+H+]=560
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:42][NH:43][O:44][CH3:45]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17](=[O:19])[N:43]([O:44][CH3:45])[CH3:42])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNOC
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)O
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Yield: 70.9 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (0.078 g ) was prepared from 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid (0.1 g, 0.179 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.017 g, 0.179 mmol) following general procedure A
Reaction SMILES: [CH:1]([NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:5](O)=[O:6])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][OH:6]
Reactant: O=CN[C@H](Cc1cccs1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@@H](CO)Cc1cccs1
Temperature: 9.5 °C
Yield: 105.8 %

Procedure:
A solution of (2R)-2-(formylamino)-3-(2-thienyl)propionic acid (3.58 g, 18.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium borohydride in tetrahydrofuran (50 ml), which was cooled to 7-12° C. (inside temperature). After the addition was finished, a solution of iodine (4.57 9, 18.0 mmol) in tetrahydrofuran (100 ml) was added dropwise. The reaction mixture was heated to reflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a freshly prepared 20% aqueous sodium hydroxide solution (200 ml). The aqueous phase was extracted with tert-butyl methyl ether (4×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 3.26 g of crude (2R)-2-methylamino-3-(2-thienyl)propan-1-ol, which was used for the following step.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:48]Cl)=[N:46][CH:47]=1)[CH2:39][CH2:40][CH3:41]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:48][C:45]2[CH:44]=[CH:43][C:42]([CH2:38][CH2:39][CH2:40][CH3:41])=[CH:47][N:46]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCc1ccc(CCl)nc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCCCc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 80.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-butyl-2-chloromethylpyridine (0.66 g) as starting materials, 5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.58 g, 3.81 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopropylcarbamate (0.41 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopropylamino)carboxamide (0.53 g, 77%) as a white solid: mp 245-247° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.87-7.69 (m, 3H), 6.58 (t, J=5.7 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H) 5.19-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.65 (d, J=6.1 Hz, 2H), 2.96-2.83 (m, 1H), 2.64-2.40 (m, 3H), 2.08-2.04 (m, 1H), 0.62-0.55 (m, 2H), 0.40-0.34 (m, 2H); 3C NMR (DMSO-d6) δ 172.75, 169.82, 167.63, 167.04, 158.69, 141.11, 134.61, 133.26, 131.49, 126.94, 121.60, 48.83, 30.93, 22.37, 21.97, 6.59; Anal. Calcd. For C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.26; H, 4.82; N, 14.85.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1>CC(C)=O>[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:11]([NH2:12])=[S:10])[CH2:16]1
Reactant: CC1(C)CCCC(N)C1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: CC1(C)CCCC(NC(N)=S)C1
Temperature: 0 °C

Procedure:
59 g (0.42 mol) of benzoyl chloride were added dropwise over the course of 10 minutes to a solution of 33 g (0.44 mol) of ammonium thiocyanate in 100 ml of absolute acetone. The mixture was refluxed for 10 minutes and then 50.8 g (0.40 mol) of 3,3-dimethylcyclohexylamine were added dropwise, and the mixture was refluxed for a further 20 minutes and then stirred into 500 ml of ice-water. The precipitated solid was filtered off with suction, washed with water, dissolved in a hot mixture of 500 ml of 10% strength sodium hydroxide solution and 125 ml of ethanol and refluxed for 30 minutes. The reaction mixture was then diluted with ice-water, and the pH was initially adjusted to 1 with concentrated hydrochloric acid and then to 9 with solid sodium bicarbonate. The resulting precipitate was filtered off with suction, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[O:21])[CH:16]=[N:17][C:18]=1[CH3:19].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC=CC=1>O>[Cl:12][C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[C:15]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH:14]=1
Reactant: Cc1ncc(C=O)cc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(C2OCCO2)cc1Cl
Yield: 86 %

Procedure:
p-Toluenesulfonic acid (5.53 mg, 0.032 mmol) was added to a mixture of 5-chloro-6-methyl-3-pyridinecarbaldehyde (for a synthesis see WO20006/137485 A1 Example 256) (250 mg, 1.607 mmol), ethylene glycol (179 μl, 3.21 mmol), and toluene (8 ml) and the mixture was heated under reflux as water was azeotropically removed (Dean-Stark). The progression was monitored by TLC (50% hexane:EtOAc) and HPLC. More ethylene glycol (180 μl) and TsOH (3 mg) were added and after 46 hr full conversion was observed by HPLC. 10% Na2CO3 and EtOAc were added. Extraction, drying (MgSO4), and filtration afforded 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine (274.3 mg, 86%) pure enough to be used in the next step.
Reaction SMILES: [CH2:1]=O.[NH2:3][O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1>CO>[Si:12]([O:11][CH2:10][C@H:9]1[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6][C@@H:5]1[O:4][N:3]=[CH2:1])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: C=O
Reactant: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: CO
Product: C=NO[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 95 %

Procedure:
A solution of HCHO (20% aqueous, 1 ml) was added dropwise to a stirred solution of 3'-O-amino-5'-O-(t-butyldimethylsilyl)thymidine (3, 7.42 g, 20 mmol) in dry MeOH (400 ml) at room temperature. After 6 h, another portion of HCHO (20% aqueous, 1.5 ml) was added and stirring continued for 16 h. The resulting solution was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give compound 10 (7.25 g, 95%) as clear foam. 1H NMR (CDCl3) δ0.1 [s, 3, (CH3)2 ], 0.9 [s, 9, (CH3)3 ], 1.9 (s, 3, CH3), 2.25-2.72 (m, 2, 2' CH2), 3.85-4.15 (2m, 3, 5' CH2, 4'H), 4.85 (m, 1, 3'H), 6.25 (dd, 1, 1'H), 6.5 and 6.95 (2d, 2, N=CH2), 7.43 (s, 1, (6H), 9.2 (br s, 1 NH).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([NH2:23])=[CH:18][CH:19]=3)[CH2:14]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl.CCN(C(C)C)C(C)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:14][C:15]3[CH:16]=[C:17]([NH:23][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(N)cc2C1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(1-methanesulfonyl-piperidin-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydro-naphthalene-2,7-diamine (200 μL of a 0.25 M solution in dichloromethane, 50 μmole) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-{7-[(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl}-isobutyramide (10.4 mg) 86, [M+H]+=450.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[NH2:11][NH:12][C:13]([NH2:15])=[S:14].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][NH:12][C:13]([NH2:15])=[S:14])=[O:6]
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: NC(=S)NNC(=O)c1ccnc(Cl)c1
Reaction time: 2 h

Procedure:
2-chloroisonicotinic acid 8.1.A (5000 mg, 31735 μmol) was refluxed in SOCl2 overnight under nitrogen. Another 4 mL of SOCl2 was added in the morning. After 2 hr., solution cleared up. The r×n was then concentrated and added to a thiosemicarbazide (2892 mg, 31735 μmol)/pyridine solution at 0° C. After 4 hr., LC/MS showed product MS along with many side peaks. The reaction was stopped and concentrated. Water and a small amount of EtOAc were added, precipitates were generated. Filtered and washed the precipitates with water 4 times. The solids were dried. LC/MS and the NMR of the precipitates showed to be the pure product. 4.05 g of the product 8.1.B (55%) was generated as a yellow powder.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][N:7]2[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=[C:6]2[CH:5]([CH3:16])[NH:4]1.CC(C)(OC([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:25][C:26](O)=[O:27])=O)C>>[ClH:1].[ClH:1].[NH2:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:25][C:26]([N:4]1[CH:3]([CH3:2])[CH2:8][N:7]2[C:9]([C:12]([F:15])([F:13])[F:14])=[N:10][N:11]=[C:6]2[CH:5]1[CH3:16])=[O:27]
Reactant: CC1Cn2c(nnc2C(F)(F)F)C(C)N1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: Cl
Product: CC1Cn2c(nnc2C(F)(F)F)C(C)N1C(=O)C[C@H](N)Cc1cc(F)ccc1F

Procedure:
The title compound is prepared by coupling 6,8-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, hydrochloride from Example 8, Step C with (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1). Treatment of the coupled product with methanolic hydrogen chloride provides the title compound.