Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)c(OC)c1
Yield: 93 %

Procedure:
4-hydroxy-3-methoxy-benzoic acid methyl ester (1.0 g, 5.5 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (1.0 g, 2.0 eq) were added and the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.53 mL, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (1.21 g, yield 93%) was recovered and used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:16][CH2:17][NH2:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N)C>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([NH:18][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCN1CCCC1
Agent: CCN
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.7 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Pyrrolidin-1-yl-ethylamine (0.201 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diispropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine as a yellow solid (0.352 g, 1.50 mmol, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:14])=[CH:4][N:3]=1.[CH3:15][O:16][C:17](=[O:29])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[CH3:15][O:16][C:17](=[O:29])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][N:8]([C:6]3[C:5]([F:14])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH3:13])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: CN(CCCO)c1nc(Cl)ncc1F
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 83, 0.60 g, 2.73 mmol) and methyl(5-hydroxy-1H-indol-1-yl)acetate (Example 9, 0.37 g, 1.82 mmol) in dichloromethane (9 mL) was added triphenylphosphine (0.70 g, 2.73 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.72 g, 2.73 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.42 g, 56%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.85 (d, 1H), 7.15-7.07 (m, 3H), 6.88-6.83 (m, 1H), 6.47-6.46 (m, 1H), 4.85 (s, 2H), 4.07 (t, 2H), 3.84 (t, 2H), 3.76 (s, 3H), 3.26 (d, 3H), 2.20-2.13 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[NH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)(C)(C)C>[CH:25]1([NH:24][C:23]([N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N=c1ccccn1CCc1ccccc1
Solvent: CC(C)(C)O
Product: c1ccc(CCn2ccccc2=NC(=NC2CCCCC2)NC2CCCCC2)cc1
Yield: 45.1 %

Procedure:
A solution of 1-(2-phenylethyl)-2-iminopyridine (5.9 g, 0.030 mole) and dicyclohexylcarbodiimide (7.26 g, 0.036 mole) in 100 ml t-butanol is heated at reflux for 24 hours. The solution is cooled and concentrated in vacuo to give a solid. The solid is recrystallized from 200 ml of hexane to give 5.48 g of the title compound which sinters at 132°C and melts at 142.5°-145°C.
Reaction SMILES: [CH:1]([Si:4]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[CH:19]=[C:20]([O:23][C@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:27]([NH2:34])[CH2:26][CH2:25]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:53][C:54](=O)[NH:55][C:56]1[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=[C:59]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:60]=1>O1CCOCC1>[C:61]([C:59]1[CH:60]=[C:56]([NH:55][C:54]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[CH2:8][CH2:7][CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:40])[CH3:39])=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:53])[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of Intermediate 84g (140 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (86.0 μL, 0.50 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 100 mg, 0.25 mmol). The reaction was heated to 60° C. overnight then further (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (50.0 mg, 0.12 mmol) was added and heating at 60° C. continued overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (70.0 mg, 34%). LCMS (Method 1): Rt 3.46, m/z 820.4 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Cl)cc(Br)c2)cc1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (8.3 g, 50.3 mmol) and 3-bromo-5-chloro-benzaldehyde (11.0 g, 50.3 mmol) in ethanol (100 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-chloro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.4 g, 35%) as a white solid: LC/MS m/e calcd for C16H13BrClNO2 M+: 366.6, observed: 366.6.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH3:38])[CH2:9][CH2:10][N:11]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:14]=1.O>ClCCl>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][N:11]([CH2:12][C:13]1[CH:14]=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:16]([NH2:19])=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH:8]([CH3:7])[CH3:38]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CCN(CCC(C)C)Cc1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 0 °C

Procedure:
A solution of lithium aluminium hydride (36 ml; 1N in THF) is added dropwise to a solution of N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-ylpropyl)amino]benzamide (1.6 g) cooled down to 0° C. The mixture is taken to a temperature of 20° C. then heated under reflux for 6 hours and hydrolyzed with water cooled down to 0° C. followed by a 1N soda solution. After the addition of dichloromethane, the mixture is filtered on celite. After decantation of the filtrate and extractions, the combined organic phases are washed with 1N soda then with salt water, dried over Na2SO4 and concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.23 g, 85% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:30][C:31]1[C:32]([N:59]2[CH2:64][CH2:63][CH:62]([C:65](O)=[O:66])[CH2:61][CH2:60]2)=[N:33][CH:34]=[C:35]([C:37](=[O:58])[NH:38][C:39]2[S:40][C:41]([CH2:50][N:51]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH3:52])=[C:42]([C:44]3[S:45][CH:46]=[C:47]([Cl:49])[CH:48]=3)[N:43]=2)[CH:36]=1>C(Cl)(Cl)Cl.C1COCC1.C(N(CC)CC)C>[ClH:30].[Cl:30][C:31]1[C:32]([N:59]2[CH2:60][CH2:61][CH:62]([C:65]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:66])[CH2:63][CH2:64]2)=[N:33][CH:34]=[C:35]([CH:36]=1)[C:37]([NH:38][C:39]1[S:40][C:41]([CH2:50][N:51]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH3:52])=[C:42]([C:44]2[S:45][CH:46]=[C:47]([Cl:49])[CH:48]=2)[N:43]=1)=[O:58]
Reactant: COCCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)O)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)N4CCOCC4)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 μl of triethylamine, 30 μl of morpholine, 45 mg of WSC.HCl and 30 mg of HOBt were added to 2 ml of a THF solution of 52 mg of 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid hydrochloride, and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform:MeOH=100:1 to 50:1, hexane:EtOAc=2:1, then chloroform:MeOH=20:1), and suspended in 2 ml of diethyl ether. 2 ml of 4M HCl-EtOAc was added, and the precipitate was collected by filtration to obtain 25 mg of 5-chloro-N-(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)-6-[4-(morpholinocarbonyl)piperidino]nicotinamide hydrochloride.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][CH2:6][C:7]1([CH3:28])[CH2:11][C:10]2[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([O:20]C(=O)C)[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:15][C:9]=2[O:8]1)=[NH:4].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[NH2:1][NH:2][C:3]([NH:5][CH2:6][C:7]1([CH3:28])[CH2:11][C:10]2[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([OH:20])[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:15][C:9]=2[O:8]1)=[NH:4]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CNC(=N)NN)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(CNC(=N)NN)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
Under a nitrogen atmosphere, 0.98 g of 1-amino-3-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]guanidine was dissolved in 50 ml of toluene. To the solution was added 10 ml of diisobutyl aluminum hydride (1.0 M in toluene) and the mixture was stirred at room temperature for 1 hour. After reaction, a saturated aqueous ammonium chloride solution was added and insoluble matters were filtered off on Celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 0.32 g of 1-amino-3-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]guanidine as a white crystal (yield 37%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([P:22]([CH2:29][SH:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:31]([NH:34][C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])[CH3:32]>CN(C=O)C>[NH:34]([C:31]([CH3:32])=[O:33])[C@H:35]([C:43]([S:30][CH2:29][P:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: SCP(c1ccccc1)c1ccccc1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)SCP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Method B (DCC coupling). Compound 20 (500 mg, 2.15 mmol) and N-acetylphenylalanine (446 mg, 2.15 mmol) were dissolved in DMF (15 mL) under Ar(g). 1,3-Dicyclohexylcarbodiimide (DCC; 489 mg, 2.37 mmol) was then added, and the reaction mixture was stirred for 12 h at room temperature. The 1,3-dicyclohexylurea (CU) by-product was removed by filtration, solvent was removed under reduced pressure, and the residue was purified by chromatography as in Method A. AcPheSCH2PPh2 was isolated as a white solid in 84% yield. Spectral data. 1H NMR (CDCl3, 300 MHz) δ 7.44-7.39 (m, 4 H), 7.35-7.33 (m, 6 H), 7.26-7.21 (m, 3 H), 7.11-7.09 (m, 2 H), 6.29 (d, J=8.4 Hz, 1 H), 4.98-4.91 (m, 1 H), 3.57-3.44 (m, 2 H), 3.09 (dd, J=14.1, 5.4 Hz, 1 H), 2.93 (dd, J=14.1, 7.5 Hz, 1 H), 1.88 (s, 3 H) ppm; 13C NMR (CDCl3, 125 MHz) δ 198.901, 169.86, 135.50, 132.62 (d, J=19.4 Hz), 129.11 (d, J-9.8 Hz) 128.79 (d, J=35.9 Hz), 128.50, 128.45, 126.99, 59.56, 37.99, 25.61 (d, J=24.4 Hz), 22.88 ppm; 31P NMR (CDCl3, 121 MHz −44.55 ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:25])[CH3:24].O>ClCCl>[C:5]([C:18]1[CH:19]=[C:10]([Br:9])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:24])[CH3:25])(=[O:7])[CH3:6]
Reactant: CCC1(CC)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)CC(C)(C)c2cc(Br)cc(C(C)=O)c2O1
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
A stirred, cooled (ice bath) suspension of aluminum chloride (1.1 g, 8.38 mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl chloride (0.6 mL, 8.38 mmol). After 5 minutes, a solution of 6-bromo-2,2-diethyl-4,4-dimethyl chroman (Intermediate 25, 1.66 g, 5.59 mmol) in dichloromethane was added. The reaction mixture was stirred for 1 h. The reaction mixture was then poured into water and extracted with diethyl ether (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.6 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[Cl:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][Br:12])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1scc(CBr)c1Cl
Yield: 57.1 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-methylthiophene (0.25 g, 1.3 mmol) in dry benzene (25 mL) were added N-bromosuccinimide (0.28 g, 1.6 mmol) and benzoyl peroxide (0.03 g, 0.13 mmol). The mixture was refluxed while irradiating with a 250 Watt lamp. After 2 hours the reaction was cooled and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 0.20 g (58% yield) of 2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene as a white solid; NMR (CDCl3) 7.6 (s, 1), 4.4 (s, 2), 3.9 (s, 3) ppm.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]#[N:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:22][CH:23]([CH3:25])[CH3:24])#[N:21]
Reactant: CC(C)CC(N)C#N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: CC(C)CC(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-4-methyl-pentanenitrile (CAN 65451-12-9) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 328.2026 (M+H)+, αD20 (MeOH)=−8.0°.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]([O:17]CC)=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].[NH3:20]>CO>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]([NH2:20])=[O:17])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCn1nc(C(=O)OCC)cc1CC(C)(C)O
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1CC(C)(C)O
Temperature: 25 °C

Procedure:
Ethyl 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate (26 g, 97 mmol) and ammonia (160 mL of a 7 N solution in methanol) were heated at 150° C. in a stainless steel reactor for 42 hours and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide as a black oil, which was treated with trifluoroacetic anhydride (40 mL, 289 mmol) and triethylamine (53 mL, 386 mmol) according to a modification of the method of Part C of Example 1253 to provide 2-(1-butyl-3-cyano-1H-pyrazol-5-yl)-1,1-dimethylethyl trifluoroacetate as a dark brown oil. The reaction with trifluoroacetic anhydride was stirred for three hours.
Reaction SMILES: [CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][N:20](CC2C=CC=CC=2)[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>CO>[CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: O=CO
Product: O=C(NC(c1ccccc1)c1ccccc1)OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzylpiperidin-4-yl benzhydrylcarbamate (46.3 g, 119 mmol) and formic acid (100 mL) in methanol (600 mL) was stirred at room temperature and nitrogen was bubbled through the reaction mixture for about 20 min. The reaction mixture was then transferred to a slurry of 10% palladium on carbon in water (75 mL.) via a thick needle and stirring was continued overnight. The reaction mixture was filtered, concentrated under reduced pressure, and dried under high vacuum overnight. The residue was then diluted with ethyl acetate and washed with satd. NaHCO3 (aq.). The organic layer was separated, concentrated under reduced pressure, diluted with 0.1N HCl (pH3) and ether. The ether layer was separated and the aqueous layer was basified with 1N NaOH (aq) to pH13-14. to give a solid which was filtered to yield piperidin-4-yl benzhydrylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:38][O:39][C:40](=[O:46])[CH:41]([CH3:45])[CH2:42][CH2:43]Cl>CN(C=O)C>[CH3:38][O:39][C:40](=[O:46])[C@@H:41]([CH3:45])[CH2:42][CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][CH:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)C(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Reaction time: 8 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (230 mg, 0.531 mmol) was dissolved in DMF (5 mL) at room temperature. Cs2CO3 (433 mg, 1.33 mmol) was added followed by 4-chloro-2-methyl-butyric acid methyl ester (120 mg, 0.796 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (1/1 hexanes/ethyl acetate—ethyl acetate gradient) to afford the product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=1)=[O:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1)=[O:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
At −78° C., oxalyl chloride (0.142 ml, 1.63 mmol) was added dropwise to a solution of dimethyl sulphoxide (0.232 ml. 3.26 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 10 min at −78° C. A solution of N-(3-(hydroxymethyl)benzyl)succinamic acid tert-butyl ester (372 mg, 1.55 mmol) in dichloromethane (5 ml) was added. The reaction mixture was stirred at −78° C. for 10 min. Triethylamine (1.08 ml, 7.77 mmol) was added. The reaction mixture was stirred at −78° C. for 5 min and then warmed to room temperature. It was stirred at room temperature for 40 min and diluted with ethyl acetate (100 ml). It was washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (150 ml) and dried over magnesium sulphate. The solvent was removed to give 312 mg of crude N-(3-formylbenzyl)succinamic acid tert-butyl ester, which was used for the next step without further purification.