Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH:44]1([NH:47][CH:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)[CH2:46][CH2:45]1>ClCCl>[CH:44]1([N:47]([CH:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)[S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:45][CH2:46]1
Reactant: CCOC(=O)C1CCC(NC2CC2)CC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A mixture of 300 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 298 mg of ethyl 4-(cyclopropylamino)cyclohexane carboxylate, and 3.0 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform only) to obtain 314 mg of methyl 4-(2-{4-[({2-[(3-{cyclopropyl[4-(ethoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow powder solid.
Reaction SMILES: C(=O)([O-])N.[F:5][C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C@@H:13]2[C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:33][O:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][C@H:14]2[OH:34])=[O:11])=[CH:8][CH:7]=1.[CH3:37][NH:38][C:39](=O)[O-:40]>ClCCl.CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C@H:13]2[C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:33][O:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][C@@H:14]2[O:34][C:39](=[O:40])[NH:38][CH3:37])=[O:11])=[CH:35][CH:36]=1
Reactant: O=C(N[C@@H]1c2cc(N3CCN(C4COC4)CC3)ccc2CCC[C@H]1O)c1ccc(F)cc1
Reactant: CNC(=O)[O-]
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)O[C@H]1CCCc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1

Procedure:
Prepare the racemic carbamate using racemic-trans-4-fluoro-N-[8-hydroxy-2-[4-(oxetan-3-yl)piperazin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-9-yl]benzamide by essentially following the procedure for Example 1, above. LC-ES/MS m/z 497 [M+H]+. Dissolve racemic-trans-9-[(4-fluorobenzoyl)amino]-2-[4-(oxetan-3-yl)piperazin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-8-yl]N-methylcarbamate (1.03 g) in dichloromethane (8 mL) and methanol (3 mL). Separate the enantiomers in 300 μL portions by SFC on a CHIRALPAK® AD-H column (2.1×25 cm, 5 μm). Mobile phase: 30% isopropanol with 0.2% isopropylamine/carbon dioxide. Flow rate: 70 mL/min. Detection: 225 nm. Obtain the title compound as isomer 1 (333 mg, 99% ee) and the 8R, 9R enantiomer as isomer 2 (359 mg, 97.5% ee). Determine enantiomeric excess by SFC on a CHIRALPAK® AD-H (4.6×150 mm, 5 μm) column using 30% isopropanol with 0.2% isopropylamine/carbon dioxide. Flow rate: 5 mL/min. Detection: 225 nm. Isomer 1 (title compound) TR=1.76 min. Isomer 2 TR=2.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(=[O:10])=[O:9].[NH2:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C@H:33]([OH:40])[C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([NH:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C:33](=[O:40])[C:34]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[O:35])=[O:30])[CH2:12]1)(=[O:9])=[O:10]
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(I)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(I)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(4-iodo-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=726.09 [M+H+].
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C>ClCCl>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:4]1[C:5]([CH3:9])=[CH:6][C:7]([OH:8])=[CH:2][C:3]1=[O:18]
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 153.1 %

Procedure:
To a suspension of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to −30° C., triethyl amine (0.5 mL, 0.004 mol) and trflic anhydride (0.7 mL, 0.0042 mol) were added and stirred for 1 h. The resulting orange solution was poured into ice cold water (25 mL) and extracted with dichloromethane (2×25 mL) The combined organic extracts were washed with water, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography using 1:1 EtOAc/hexane v/v to afford 1.0 g (85%) the title compound as a light brown solid: 1H-NMR (CDCl3/400 MHz) δ 7.32 (m, 1H), 7.0-6.85 (m, 3H), 6.18 (s, 1H), 5.32 (s, 2H), and 2.34 (s, 3H); ES HRMS m/z 443.9492 (M+H C14H11NO4BrF4S requires 443.9528). Step 4: Preparation of 3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:9]=1)[Si:23]([CH3:25])([CH3:24])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)OC(C)(C)C)[Si](C)(C)C)cc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a stirred solution of tert-butyl(3-bromo-4-methylphenyl)carbamate (2.86 g, 10 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 8.8 mL, 22 mmol) at −78° C. and the solution was stirred at this temperature for another 30 min. Trimethylsilyl chloride (2.39 g, 22 mmol) was added at −78° C. and the reaction mixture was then allowed to warm up to r.t. and stirred at r.t. for 1 hr. The reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel flash chromatography (eluted with 20% EtOAc in Hexanes) to give the desired product as a white solid (3.33 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18].N1([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:28][CH2:27]2)=[O:25])C=CN=C1.CC(C)([O-])C.[K+].Cl>C(O)(CC)(C)C.C1COCC1.CC(C)=O.O>[O:43]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:17][C@@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C:5]3[CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]([NH2:1])=[C:3]([Cl:18])[CH:4]=3)=[O:25])[CH2:31][CH2:30]2)[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34]1
Reactant: O=C1Nc2ccccc2CCN1C1CCN(C(=O)n2ccnc2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](O)C(=O)O)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 kg (17.63 mol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl]-2-hydroxy-propionic acid (G) and 6.28 kg (19.39 mol) 1-(1H-imidazol-1-yl-carbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidine (F) were suspended in 40.0 L tert.-amylalcohol, before 20 L solvent were distilled off under normal pressure. Then the reaction mixture was cooled to 25° C., 21.76 kg (38.78 mol) potassium tert.butoxide solution in THF was added, before the mixture was heated to 35° C. for 1.5 hours. After the reaction was complete the mixture was cooled to 25° C. cooled and 9.64 kg (79.33 mol) hydrochloric acid (30%), 25.0 L water and 25.0 L acetone were added successively, before the mixture was inoculated with 5 g ethyl (1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-carboxy-2-[4-amino-3-chloro-5-trifluoromethyl-phenyl]-1-piperidinecarboxylate. After stirring overnight the suspension was cooled to 0° C. and stirred for a further hour. The product was separated off, washed twice with 15.0 L water and 15.0 L acetone and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[C:7]([F:35])[CH:6]=1)=[O:4].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:37][OH:38])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:13][CH:12]=2)=[C:7]([F:35])[CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)c(F)c1

Procedure:
In analogy to example 74, step 7, from 2-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.8:1) as a white foam, MS (ESI+): m/z=483.2073 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:7][CH:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(N)=NN1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5), 5.0 ml. of acetic anhydride and 100 mg. of 4-dimethylaminopyridine is allowed to stand at room temperature for 3 hours. The mixture is filtered to give a white solid. The solid is dissolved in dichloromethane and is columnized and recrystallized as for Example 14 (B) to give 0.90 g. of the desired product as colorless plates, m.p. 144.5-146.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.C(NC1N=C(C(O)=O)C=C(C)N=1)C.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH2:32]([NH:31][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: CCNc1nc(C)cc(C(=O)O)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-ethylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.86 min; [M+H]+=457.27. 1H NMR (D6-DMSO): δ 1.16 (t, J=7.0 Hz, 3H), 2.34 (s, 6H), 2.41 (s, 3H), 3.25 (m, 1H), 3.35-3.50 (m, 3H), 3.70-3.80 (m, 2H), 3.84 (d, J=5.3 Hz, 2H), 3.96 (m, 1H), 5.29 (d, J=5.0 Hz, 1H), 5.55 (t, J=5.8 Hz, 1H), 7.28 (s, 1H), 7.63 (s br, 1H), 7.69 (t, J=5.3 Hz, 1H), 7.76 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:11][CH2:10]1.[O:30]=[C:31]1[CH2:36][O:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[O:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one trifluoroacetate (Intermediate 46) (0.4 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (80 mg, 0.44 mmol) and sodium cyanoborohydride were reacted as described under Example 21, but, the reaction was stirred at room temperature overnight after sodium cyanoborohydride addition to give the title compound as a free base, 30 mg (17%).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-dodecylamine (1.049 g, 5.59 mmol), triethylamine (0.86 ml, 6.15 mmol) and acetyl chloride (0.44 ml, 6.15 mmol) in dichloromethane (10 ml) was stirred at room temperature for 3h. The mixture was quenched with water and the organic phase was separated. Evaporation of the dried (magnesium sulfate) organic phase gave a solid, which was recrystallized from hexane to give the titled amide.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][NH:30][C:31](=[O:37])[CH2:32][C:33]([F:36])([F:35])[F:34])(C)(C)C.CCOC(C)=O>C1COCC1>[Cl:41][C:40]1[CH:39]=[CH:38][C:28]([CH2:29][NH:30][C:31](=[O:37])[CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
TBAF (1M in THF, 9.10 mL, 9.10 mmol) was added to a sol. of N-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-3,3,3-trifluoro-propionamide (1.80 g, 4.55 mmol) in THF (45 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NH4Cl (3×) and water (4×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 70:30) yielded the title compound (835 mg, 65%). LC-MS: tR=0.76 min; ES+: 323.02.
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][NH2:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]([O:18][Si:19]([CH2:20][CH3:21])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:16][NH:17][CH2:5][C:2]1([CH3:1])[CH2:3][CH2:4]1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Reactant: CC1(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1(C)CC1)c1c(Cl)cccc1Cl
Reaction time: 0.75 h
Yield: 62.8 %

Procedure:
To a mixture of 1-methylcyclopropanecarbaldehyde (32.8 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated then purified by prep TLC eluted with 5% MeOH/DCM to provide 2-(2,6-dichlorophenyl)-N-((1-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)ethanamine (95 mg, 0.245 mmol, 62.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.28-7.30 (m, 2H), 7.12-7.16 (m, 1H), 5.65 (br. s., 1H), 3.37-3.44 (m, 1H), 2.82-2.90 (m, 1H), 2.69 (br. s., 1H), 2.48 (d, J=11.86 Hz, 1H), 1.60 (br. s., 1H), 1.15 (s, 3H), 0.87-0.92 (m, 9H), 0.51-0.63 (m, 6H), 0.28-0.44 (m, 4H); LCMS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[CH2:7][CH2:8][NH2:9].[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:4]([Br:10])[S:3][C:2]=1[Br:1]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCc1cc(Br)sc1Br
Solvent: CC#N
Product: OC(CNCCc1cc(Br)sc1Br)c1ccccc1

Procedure:
A solution of 2,5-dibromothiophene-3-ethylamine (31.6 g) and styrene oxide (13.3 g) in acetonitrile (135 ml) was heated under reflux for 24 hours. After standing at room temperature, brown crystals were filtered contaminated by traces of black tar. Recyrstallisation from acetonitrile (45 ml) with carbon treatment gave the title product (m.p. 94°) as tan crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)Br
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1Cl)C(C)C
Yield: 94 %

Procedure:
To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of a sodium hydride dispersion 78% while nitrogen gas is introduced. After stirring till foaming has ceased, there are added 15 parts of 2-bromopropane and the whole is stirred for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated, yielding 24.5 parts (94%) of methyl 2,4-dichloro-α-(1-methylethyl)benzeneacetate as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reaction time: 16 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 5.4 g of 2-fluoronitrobenzene and 1.0 g of sodium bicarbonate is stirred at 160°-165° C. under nitrogen, for 16 hours. Thereafter, the mixture is permitted to cool before sequentially being quenched with water and extracted thrice with ether. The combined ether extracts are shaken with a large excess of 1N hydrochloric acid. The acidified layer is basified providing a reddish oil which upon drying over magnesium sulfate and then cooling leaves an orange solid. The solid is recrystallized from an ether-pentane mixture to provide prisms, mp 130°-131° C. of 6-chloro-1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)([Cl:27])=O>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:27])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 86.5 %

Procedure:
Dimethylformamide (0.5 ml) was added to a suspension of 7-(benzyloxy)quinazolin-4-(3H)-one (5.04 g, 20 mmol) in thionyl chloride (50 ml) and the mixture heated at reflux for 2 hours. The thionyl chloride was removed in vacuo and the residual oil dissolved in dichloromethane (100 ml). This solution was slowly added to an aqueous saturated solution of sodium bicarbonate (100 ml) and the organic phase recovered. The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organics dried and concentrated to yield 7-(benzyloxy)-4-chloroquinazoline (4.68 g, 86.5% yield):
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9][N:8]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl>[Si:17]([O:16][CH2:15][CH2:14][O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:6])[N:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCCOc1ccnc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Imidazole (389 mg, 5.72 mmol) was added to a suspension of 2-[(2-chloropyrimidin-4-yl)oxy]ethanol (416 mg, 2.38 mmol) in dichloromethane (9.5 mL) at 0° C. tert-Butyldimethylsilyl chloride (424 mg, 2.81 mmol) was added and the reaction mixture stirred at room temperature for 2 h. The reaction was quenched with water and the organic layer separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-chloropyrimidine (678 mg, 2.35 mmol, 99% yield) as a clear, yellow oil. MS ESI: [M+H]+ m/z 289.1.
Reaction SMILES: [CH3:1][S:2][CH3:3].[Na].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=C(F)[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[N:10][CH:11]=1>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:1]([S:2][CH3:3])[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[N:10][CH:11]=1
Reactant: CSC
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a stirring solution of sodium methylsulfide (0.13 g, 2 mmol) in N,N-dimethylformamide (20 mL) was added N-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide (0.48 g, 1.6 mmol) and additional N,N-dimethylformamide (5 mL). The reaction solution was stirred overnight at room temperature and concentrated in vacuo. The resulting residue was partitioned between dichloromethane and water and the layers separated. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was slurried in diethyl ether and filtered to give 0.33 g (63%) of a yellow solid.