Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Li+].CC([N-]C(C)C)C.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[CH2:27][CH:14]1[CH2:15][CH2:16][N:12]([C@H:11]2[CH2:10][CH2:9][C:4]3([O:5][CH2:6][CH2:7][O:8]3)[CH2:3][C@H:2]2[CH3:1])[C:13]1=[O:17]
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: C[C@@H]1CC2(CC[C@@H]1N1CCCC1=O)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[C@@H]1CC2(CC[C@@H]1N1CCC(Cc3ccc(Cl)cc3Cl)C1=O)OCCO2
Yield: 56.5 %

Procedure:
Using the procedure to synthesize Example 1 and using reagent 1-(cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (Preparation 45) (2.49 g, 10.4 mmol), LDA (1.5M, 8.3 mL, 12.5 mmol) and 1-(bromomethyl)-2,4-dichlorobenzene (4.07 g, 20.8 mmol) yields 2.34 g (56%) of 3-(2,4-dichloro-benzyl)-1-(cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]Br.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.O>[Br:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[OH:9])=[CH:15][CH:14]=1
Reactant: CC(C)[Si](Oc1ccc(C(O)c2ccc(Cl)cc2)cc1)(C(C)C)C(C)C
Reactant: BrCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccc(OCCCCCCCCBr)cc1
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
in THF (30 mL) was added n-BuLi (1.6 M. 5.8 mmol). After 30 minutes 4-(triisopropylsilyloxy)benzaldehyde (1.5 g, 5.3 mmol) in THF (2 mL) was added into the reaction mixture. The reaction mixture was warmed to room temperature and quenched with aq. NH4Cl. The water phase was extracted with EtOAc and the combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide the crude product. Purification by silica gel chromatography provide (4-chlorophenyl)(4-(triisopropylsilyloxy)phenyl)methanol (1.7 g, 4.2 mmol). (4-Chlorophenyl)(4-(triisopropylsilyloxy)phenyl)methanol (1.7 g, 4.2 mmol) was dissolved in THF (5 mL) and TBAF (1.0 M, 6.0 mmol) was added. After 15 minutes, the reaction mixture was quenched with MeOH (10 mL), concentrated, and the residue was purified by silica gel chromatography to afford4-((4-chlorophenyl)(hydroxy)methyl)phenol (963.1 mg, 4.1 mmol). This was subjected to alkylation with 1,8-dibromooctane (3.3 g, 12.3 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (45 mL). After 12h the reaction mixture was diluted with water (150 mL) and water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)phenyl)(4-chlorophenyl)methanol (1.6 g, 3.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][N:41]([CH2:51][CH2:52][O:53][CH3:54])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:51][CH2:52][O:53][CH3:54])=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 763.4 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1cccc(S(N)(=O)=O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: COc1cccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-methoxybenzenesulfonamide: 1H-NMR (CDCl3) δ 7.47-7.09 (13H, m), 6.36 (1H, br.s), 3.81 (3H, s), 3.49-3.43 (2H, m), 2.83 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.24 (3H, s).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]2)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[CH:1]([CH:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]2)[CH:15]=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CCC(C(C)C)CC4)ccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C1CCC(Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
Ethyl 1-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (120 mg, 0.27 mmol) was dissolved in EtOH (5 mL). NaOH (55 mg, 1.4 mmol, 5 eq) was added in one portion at room temperature. The mixture was stirred at 80° C. for 16 h. Solvent was removed and the residue was dissolved in H2O (3 mL). 1 M aqueous HCl was added to adjust pH=7. The mixture was filtrated to give 1-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid as a white solid (85 mg, yield: 61%). ESI-MS (M+1)+: 410.3, HPLC: 100.00%. 1H NMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 7.96 (s, 1H), 7.86-7.84 (m, 2H), 7.62-7.60 (m, 1H), 7.39 (s, 1H), 7.24 (d, J=9.2 Hz, 1H), 4.77-4.76 (m, 1H), 4.42-4.36 (m, 2H), 3.40 (s, 2H), 2.95-2.93 (m, 2H), 2.50-2.49 (m, 1H), 2.03-2.00 (m, 4H), 1.85-1.75 (m, 2H), 1.62-1.34 (m, 7H), 1.19-1.12 (m, 1H), 0.88 (d, J=6.8 Hz, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].C(O)(=O)C>C(OCCCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@H]1C[C@H](OC(C)=O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Solvent: CCCCOC(C)=O
Solvent: CC(=O)O
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
In 10 ml of butyl acetate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was stirred in an atmosphere of argon gas under heating at 100° C. for 12 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 100 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7 -diene showing the following physical properties.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>ClCCl.CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([NH2:10])=[O:9])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)[C@H]1CCCC[C@H]1N
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 53.2 %

Procedure:
A mixture of (1S,2R)-2-aminocyclohexanecarboxylic acid amide (16.2 mmol), 4-chlorobenzenesulfonylchloride (6.84 g, 32.4 mmol), and triethylamine (20 mL, 143 mmol) were stirred in dichloromethane/DMF (500 mL/100 mL) at room temperature for 6 h. The crude mixture was poured into 1 M hydrochloric acid (500 mL). The organic layer was collected and washed with with water (2×500 mL). Hexanes (50 mL) were added to the organic layer. The combined mixture was sequentially washed with water (500 mL) and brine (50 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (solvent gradient: methanol/chloroform, 0.25% to 5.0%) to afford 2.73 g (53% yield, 5 steps) of (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide. An analytical sample was obtained after recrystallization from ethyl acetate/hexanes: 1H NMR (400 MHz, DMSO-d6) 7.82 (d, 2 H, J=8.5), 7.64 (d, 2 H, J=8.6), 7.57 (d, 1 H, J=7.1), 7.22 (s, 1 H), 6.79 (s, 1 H), 3.43 (m, 1 H), 2.36 (m, 1 H), 1.72 (m, 2 H), 1.46 (m, 3 H), 1.17 (m, 3 H); MS m/e 339.1 (M+Na)+. Anal. calcd. for C13 H17ClN2O3S: C, 49.28; H, 5.40; N, 8.84. Found: C, 49.55; H, 5.24; N, 8.78. Optical rotation: [α]D=−55.8 (c=6.78 mg/mL, DMF).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:4]=2[N:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:8]=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1>>[NH2:35][C:36]1[N:37]=[CH:38][C:39]([C:2]2[C:3]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:4]=3[N:5]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:17]4[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:19]=3)[N:8]=2)=[CH:40][CH:41]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(Cl)c3cc(Cl)ccc32)cc1
Product: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(c3ccc(N)nc3)c3cc(Cl)ccc32)cc1

Procedure:
5,7-Dichloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.10 g, 0.20 mmol) and 2-aminopyridine-5-boronic acid pinacol ester were reacted according to the corresponding procedure described in Example 12 to yield intermediate 5-(6-aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. (77 mg, 69%). 5-(6-Aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (77 mg, 0.14 mmol) was dissolved in anhydrous anisole (2 mL) under a nitrogen atmosphere, and aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The mixture was heated to 80° C. for 1 hour then cooled to ambient temperature and an additional amount of aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The solution was heated to 80° C. for 1 hour, cooled, poured into ice, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer dried with sodium sulfate, decanted and concentrated in the presence of silica gel. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided 5-(6-aminopyridin-3-yl)-7-chloro-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (25 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ 3.47 (m, 2H) 3.71 (m, 1H), 6.40-6.46 (m, 2H), 7.20-7.26 (m, 2H), 7.42-7.62 (m, 5H), 7.78-7.87 (m, 4H), 10.64 (s, 1H); ESI m/z measured 427.1324 [M+H]+. calculated 427.1326.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH:5]1[CH2:11][CH2:12][C:13](=[O:15])[CH3:14].[CH2:17]([O:19][C:20](=[O:26])[C:21](OCC)=[O:22])[CH3:18].CC[O-].[Na+]>CCO>[CH2:17]([O:19][C:20](=[O:26])[C:21](=[O:22])[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:5]1[CH:6]([CH3:10])[CH2:7][CH2:8][CH2:9][C:4]1([CH3:3])[CH3:16])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCC1C(C)CCCC1(C)C
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCC1C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (0.6447 g, 25.52 mmol) was added slowly to a NaCl ice bath containing EtOH (10 mL, 2.6 M) stirring under N2. 4-(2,2,6-trimethylcyclohexyl)-butan-2-one (5.0072 g, 25.50 mmol) and diethyloxalate (3.7241 g, 25.48 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. The reaction quickly solidified. An additional 10 mL EtOH was added, and the reaction was allowed to stand for another 3 h. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 1:1 Hexanes:CH2Cl2): Only pure fractions were combined and concentrated to obtain 52. 1H (CDCl3, 400 MHz): δ 14.51 (1H, broad s), 6.34 (1H, s), 4.34 (2H, q, J=7.1 Hz), 2.44 (2H, t, J=8.3 Hz), 1.96-1.84 (1H, m), 1.68-1.22 (m), 1.36 (3H, t, J=7.1 Hz), 1.18-0.98 (m), 0.94 (3H, s), 0.87 (3H, s), 0.85 (3H, d, J=7.3 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 203.45, 167.17, 162.40, 101.80, 62.71, 49.28, 42.60, 30.46, 20.86, 14.27 ppm. Partial DEPT (CDCl3, 100 MHz): CH3 carbons: 14.27; CH2 carbons: 62.71; CH carbons: 101.80 ppm. HPLC: 12.576 min.
Reaction SMILES: C(O)(=O)C(O)=O.CS(C)=O.[F:11][CH2:12][CH2:13][OH:14].[N+:15]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([O-:17])=[O:16]>C(Cl)Cl.O.CCN(CC)CC>[F:11][CH2:12][CH:13]([OH:14])[CH:18]([N+:15]([O-:17])=[O:16])[CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21]
Reactant: OCCF
Reactant: CC(C)(C)OC(=O)CC[N+](=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CC(C(O)CF)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
A solution of oxalic acid (1.9 mL, 21.8 mmol) in dry CH2Cl2 (100 mL) was cooled to −78° C., a solution of DMSO (3.0 mL, 42.3 mmol) in dry CH2Cl2 (10 mL) was added with stirring in such a rate that the temperature was kept at −50 to −60° C. After 5 min stirring, a solution of 2-fluoroethanol (1.2 mL, 18.4 mmol) in dry CH2Cl2 (10 mL) was added, and stirring was continued for an additional 15 min, then dry Et3N (13.5 mL) was added. The reaction mixture was stirred for 15 min, then allowed to warm to rt. To the reaction mixture was added a solution of t-butyl 3-nitropropionate (2.87 g, 16.38 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt for 3 h, then poured into water (100 mL). The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×50 mL). The CH2Cl2 solution was washed with brine, dried and evaporated. The residue was purified by chromatography twice over silica gel (hexane-EtOAc, 7:3) to give 950 mg (24.5%) of the titled product as a colorless viscous oil. 1H NMR (CDCl3), 1.450 (s, 9H), 2.80-2.90 (m, 2H), 3.12-3.20 (m, 1H), 4.41-4.59 (m, 2H), 4.57-4.59 (m, 1H), 4.95-5.01 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH2:25]([Li])[CH:26]([CH3:28])[CH3:27]>O1CCCC1>[CH3:4][C:2]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:6])([CH3:1])[CH3:3]
Reactant: [Li]CC(C)C
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R,E)-2-methyl-N-((4′-(trifluoromethyl) biphenyl-4-yl)methylene)propane-2-sulfinamide (25.0 g, 70.7 mmol) and tetrahydrofuran (140 mL) and cooled down to −78° C. To this solution was added isobutyllithium (1.6M in heptane; 50.8 mL) dropwise over 20 minutes. The reaction was allowed to stir at −78° C. for 30 minutes. LC-MS analysis showed complete conversion of the starting material and the formation of two product diastereomers (4.6:1). The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1-10% ethyl acetate/dichloromethane) allowed isolation of the major isomer (the less polar isomer), (R)-2-methyl-N—((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 74.2%) as a colorless gum. 1H NMR (400 MHz, CDCl3, δ): 0.91 (d, 3H) 0.96 (d, J=6.44 Hz, 3H) 1.24 (s, 9H) 1.49-1.59 (m, 1H) 1.63-1.72 (m, 1H) 1.84-1.94 (m, 1H) 3.38 (br. s., 1H) 4.46 (dd, J=8.19, 6.83 Hz, 1H) 7.43-7.46 (m, 2H) 7.56-7.60 (m, 2H) 7.68-7.70 (m, 4H). MS (M+1): 412.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([Cl:16])=[CH:4][N:3]=1.[Br:17][CH2:18][C:19](Br)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]([C:7]1[C:2]([NH:1][C:19](=[O:20])[CH2:18][Br:17])=[N:3][CH:4]=[C:5]([Cl:16])[N:6]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Br)CBr
Reactant: Nc1ncc(Cl)nc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ncc(Cl)nc1C(=O)c1ccccc1

Procedure:
2-Amino-3-benzoyl-5-chloropyrazine (0.9 g or 4 mmol) was reacted as described in Example 5 with 8.1 g. (0.04 mol) of 2-bromoacetyl bromide in 25 ml. methylene chloride and 25 ml. of 10% aqueous sodium carbonate solution. The same work up yielded 1 g. (71%) of the above-named product with a melting point of 120°-125° dec. Recrystallization from methylene chloride/petroleum ether afforded colorless needles with a melting point of 124°-126° dec.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10].CS(O[CH:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]1)(=O)=O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc(F)ccc1O
Reactant: CN1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(F)cc2C(N)=O)C1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a suspension of 0.44 g (60% in oil, 0.011 mole) of sodium hydride in 10 ml of dimethylformamide was added 1.55 g (0.01 mole) of 5-fluoro-2-hydroxybenzamide in 10 ml of dimethylformamide under nitrogen atmosphere at room temperature. The reaction mixture was heated to 60° C. and 1.80 g (0.01 mole) of 1-methyl-3-pyrrolidinol methane sulfonate (ester) was added. The reaction mixture was then heated to 100° C. for 18 hr. The dimethylformamide was removed by rotary evaporation at 70° C., 0.5 mm Hg. The residue was taken up in 200 ml of methylene chloride, washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water. The organic phase was extracted with 2×50 ml of 1N hydrochloric acid. The combined aqueous extracts were washed with 50 ml of methylene chloride, made basic with concentrated sodium hydroxide and extracted into 2×50 ml of methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was crystallized from hexane to give 1.0 g of off-white crystals, m.p. 90°-93° C.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11]2)=[O:7])=[C:4]([OH:26])[CH:3]=1.[CH2:27](Br)[CH2:28][CH2:29][CH3:30]>[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: CCCCBr
Reactant: Nc1cc(O)c(C(=O)NCC2CN(Cc3ccccc3)CCO2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 119.6 %

Procedure:
To a stirred solution of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-hydroxybenzamide (4.0 g) in 1N aqueous sodium hydroxide solution (32 ml), tetrabutylammonium bromide (3.4 g) and a solution of butyl bromide (4.3 g) in dichloromethane (32 ml) are added. The reaction mixture is stirred at 25° C. for 15 hours and concentrated under reduced pressure. To the residue is added ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel with methanol-chloroform (5:95) to give the title compound (5.5 g) as an oil. The free base thus obtained is dissolved in hot ethanol (20 ml), and fumaric acid (1.5 g) is added. The solution is stirred for some time. The precipitate is collected and recrystallized from ethanol to give the fumarate hemihydrate (4.6 g) of the title compound, mp 188°-190° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (4.03 g) in absolute ethanol (100 mL) was added DIEPA (5.3 mL) and 5-methyl-1H-pyrazol-3-amine (2.03 g). The resulting solution was stirred at room temperature for 6 hours. The precipitation was filtered and washed with cold ethanol. The compound was dried by vacuum oven give 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (3.7 g). m/z 262. A mixture of morpholine (0.181 mL), 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg) and DIPEA (0.505 ml) in absolute ethanol (10.0 ml) was heated at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (236 mg). 1H NMR δ 12.05 (bs, 1H) 9.57 (s, 1H) 6.21 (s, 1H) 3.67 (t, 4H) 3.57 (t, 4H) 2.22 (s, 3H); m/z 313.