Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:20]([C:25]#[N:26])([CH3:24])[C:21](O)=O)[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:60][C:61]1[CH:62]=[C:63]([NH2:68])[C:64]([NH2:67])=[CH:65][CH:66]=1>C(Cl)Cl>[Br:60][C:61]1[CH:66]=[CH:65][C:64]2[NH:67][C:21]([C:20]([C:12]3[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]4[C:11]=3[CH:10]=[CH:9][NH:8]4)([CH3:24])[C:25]#[N:26])=[N:68][C:63]=2[CH:62]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(C#N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c2[nH]ccc2c1C(C)(C#N)c1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (±)-2-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-2-cyanopropanoic acid (Example 155-E) (1.4 g, 3.91 mmol) in DCM (39.1 ml) at 0° C. was added DIPEA (2.05 ml, 11.72 mmol) followed by HBTU (1.926 g, 5.08 mmol) and 4-bromobenzene-1,2-diamine (1.096 g, 5.86 mmol) at 0° C. and stirred in the ice bath for 20 minutes. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water, the layers were separated and the organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in acetic acid (7 mL) and heated at 85° C. for 4 hours. The reaction was cooled to 0° C. and quenched with a saturated solution of sodium bicarbonate, diluted with water and EtOAc. The layers were separated and the organic layer was removed, dried over Na2SO4 and concentrated. The crude product was purified via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 409.3, 411.3 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC(C)OC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 63.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.38 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride (1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: NCCCc1ccccc1
Product: O=C(NCCCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-phenylpropylamine as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N+:15]([O-])[CH:16]=[CH:17][C:12]2=[N:11]1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:22][C:14]1[C:13]2=[CH:19][N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[CH:17]=[CH:16][N:15]=1
Reactant: [O-][n+]1ccc2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Fc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Temperature: 85 °C
Yield: 47 %

Procedure:
2-(2,6-Dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.4 g, 4.7 mmol) was slowly added to phosphorous oxychloride (10 mL). Tetrabutylammonium chloride (1.31 g, 4.7 mmol) was then added and the reaction mixture was heated at 85° C. for 45 minutes. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (706 mg, 47% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.72 (d, J=6.3 Hz, 1H).
Reaction SMILES: C(Br)CC.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:30][C:31]1[C:41]2[N:40](CCC)[C:39](=[O:45])[C:38]([CH3:47])([CH3:46])[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:35]=2[CH:34]=[C:33]([N+:55]([O-:57])=[O:56])[CH:32]=1>CCOCC.CCCCCC>[Cl:30][C:31]1[C:41]2[NH:40][C:39](=[O:45])[C:38]([CH3:47])([CH3:46])[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:35]=2[CH:34]=[C:33]([N+:55]([O-:57])=[O:56])[CH:32]=1
Reactant: CCCN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCBr
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 32 g (0.088 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and propyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 3 days, 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-1-propyl-2H-1,4-benzodiazepin-2-one of melting point 142°-143° (ether/n-hexane).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
tert-Butyl 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (3.65 g, 10.9 mmol) was taken into methanol (40 mL) followed by addition of 1M aqueous sodium hydroxide (15 mL) and THF (15 mL), and the mixture was heated at 50° C. for one hour. An additional portion of 1 M aqueous sodium hydroxide (10 mL) was then added and heating was continued an additional two hours. The mixture was then cooled to room temperature and concentrated to remove organic solvents. The aqueous residue was partitioned with ethyl ether and the organic layer was discarded. The aqueous phase has carefully brought to pH 5-6 by addition of 1M aqueous hydrochloric acid to give a thick white suspension. The solid was collected by filtration and dried to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g). 1H NMR (400 MHz, DMSO-d6): 12.57 (br s, 1H), 8.64 (s, 1H), 7.95 (d, 1H), 6.86 (d, 1H), 3.67-3.62 (m, 4H), 3.45-3.40 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:27]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][CH2:39][CH3:40])[CH:33]=[C:32]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[C:1]([C:2]([CH3:4])([CH3:3])[CH:27]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][CH2:39][CH3:40])[CH:33]=[C:32]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])[OH:28])([OH:6])=[O:5]
Reactant: CC(C)C(=O)O
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C(O)C(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
Isobutyric acid (1.2 g, redistilled) was slowly added dropwise to a stirred solution of lithium di-isopropylamide [prepared from di-isopropylamine (2.74 g) and n-butyl lithium (13.6 ml of a 2M solution in hexane)] in dry tetrahydrofuran (50 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 40 min, heated to 45° for 2 hr, and allowed to cool to room temperature. This solution was then added dropwise to a stirred solution of methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (3.0 g, prepared as described in Example 61, part a) in dry retrahydrofuran (25 ml) under an atmosphere of nitrogen. After 1 hr, the mixture was poured into 20% (w/v) aqueous citric acid solution (150 ml) and extracted with ethyl acetate. The combined extracts were washed (water (twice), brine), dried (MgSO4), and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 80:20:2 toluene ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-1-hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.47 g, 40%) as a yellow foam: partial NMR (250 MHz, DMSO-d6): 0.81(m, 6H, CH2CH3, C(CH3)), 0.97(s, 3H, C(CH3)), 1.71(m, 2H, CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.05(m, 4H, NCH2, ArCH2Ar'), 4.85(m, 1H, CH(OH), 5.29(d, 1H, CH(OH), 12.02(br s, 1H, COOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccnc(Cl)n1
Reactant: CCCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)c1ccnc(Cl)n1
Yield: 85 %

Procedure:
A solution of 0.52 g (2.93 mmol) of 2-chloropyrimidine-4-carboxylic acid chloride in 10 ml of butanol was stirred for 1.5 hours at room temperature. Then the reaction solution was poured on 80 ml of NaHCO3 solution and extracted three times with 60 ml of ethyl acetate each. The combined organic phase was washed with 60 ml of saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation on a rotary evaporator. After drying of the product on a high vacuum, 0.53 g of product was obtained as a white solid, corresponding to a yield of 85 percent relative to the 2-chloropyrimidine-4-carboxylic acid chloride used. The melting point of the product was 67.9° to 68.8° C. Other data for the product was:
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:11]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].ClC1C=CC=C(C)C=1O.C([SiH](C)C)(C)(C)C.BrN1C(=O)CCC1=O.[CH3:49][O:50][C:51](=[O:61])[C:52]1[CH:57]=[C:56]([CH3:58])[C:55]([Br:59])=[C:54]([SH:60])[CH:53]=1>C(Cl)(Cl)Cl.CO>[CH3:49][O:50][C:51](=[O:61])[C:52]1[CH:57]=[C:56]([CH3:58])[C:55]([Br:59])=[C:54]([S:60][CH2:9][C:10]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:11]=2[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:53]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc(C)c(Br)c(S)c1
Agent: C[SiH](C)C(C)(C)C
Agent: Cc1cccc(Cl)c1O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl amine (36 mL, 0.263 mol) was added to a solution of (2-bromomethyl-6-chloro-phenoxy)-tert-butyl-dimethyl-silane (72 g, 0.214 mol) [prepared from 6-chloro cresol by protecting the hydroxy group with t-butyldimethylsilane followed by bromination using N-bromosuccinimide] and compound of Example 1f (43 g, 0.164 mol) in chloroform (600 mL) at 5° C. over a period of 20 min. The reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was washed with water (2×200 mL) and brine (100 mL). The solvent was removed under reduced pressure and to the oily mass obtained, methanol (300 mL) was added with stirring. The crystalline solid obtained was filtered, washed with methanol and dried to obtain the title compound. Yield: 70 g, (83%); 1H NMR (CDCl3, 300 MHz): δ 0.28 (s, 6H, 2CH3), 1.03 (s, 9H, 3CH3), 2.45 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 4.19 (s, 2H, CH2), 6.89 (t, 1H, Ar), 7.24 (t, 1H, Ar), 7.32 (d, 1H, Ar), 7.61 (s, 1H, Ar), 7.69 (s, 1H, Ar); MS: m/e (ES−) 515 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([Cl:25])=[C:12]2[CH2:26][C:27]([NH2:29])=[O:28])C.[OH-].[Na+].Cl>CCO>[NH2:29][C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[Cl:25]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(Cl)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)Cc1c(Cl)n(Cc2ccccc2)c2ccc(OCCCC(=O)O)cc12
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A solution of 140 mg (0.43 mmol) of 2-chloro-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 11) in 20 mL of methylene chloride was treated with 2 mL of 1M BBr3/CH2Cl2, stirred for 1.5 hours, stirred with aqueous HCl, the CH2Cl2 solvent separated, and washed with water, saturated NaCl solution and dried (Na2SO4). On concentrating at reduced pressure, there was obtained 140 mg of crude 2-chloro-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide. This material was dissolved in 15 mL of DMSO, 20 mg of 60% NaH/mineral oil added, and after 5 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. The reaction mixture was heated by oil bath at 70° C. for 70 minutes. After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution and dried (Na2SO4). After concentrating, a residue was obtained that was chromatographed on silca (eluted with CH2Cl2→3% MeOH/CH2Cl2) to give 105 mg of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (105 mg) was dissolved in 15 mL of EtOH, 1 mL of 5N NaOH added, and the solution stirred for 18 hours. The mixture was made acidic with 5N HCl, and extracted with EtOAc. The EtOAc solution was washed with saturated NaCl solution, dried (Na2SO4) and concentrated at reduced pressure. The residue was dissolved in MeOH/CH2Cl2, the solution concentrated, to give 75 mg (80% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 198-200° C.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH:25]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][OH:18])(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](OCCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.3 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved 2-[7-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]heptyl]-1,4-difluorobenzene (786 mg, 1.23 mmol), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 4.0 ml, 4.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (2 ml), the mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (403 mg, 1.00 mmol, 81%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].[CH3:28]I.Cl>COCCOC>[CH3:28][N:3]1[C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(F)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1=C(C)N(C)C(C)=C(C(=O)OCC)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.78 g (0.008 mol) of diethyl 2,6-dimethyl-4-(4-fluorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate dissolved in 25 ml of 1,2-dimethoxyethane, and 0.30 g (0.01 mol) of 80% strength sodium hydride and, after 30 min, 1.43 g (0.01 mol) of methyl iodide are added. The mixture is stirred at room temperature for 3 hours, neutralized with dilute hydrochloric acid and evaporated in vacuo. The residue is purified by chromatography on silica gel (methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>COCCOC.C(OCC)(=O)C>[CH3:28][S:29]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:8]2[NH:7][C:6]3[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:11](=[O:12])[NH:10][C:9]=2[CH:13]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2cc(CCO)ccc2Nc2cc(Cl)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A mixture of Example 204A (1.8 g, 5.58 mmol) in DME (30 mL) was treated with triethylamine (2.33 mL, 16.7 mmol), followed by methanesulfonyl chloride (648 μL, 8.4 mmol) and stirred at ambient temperature for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated to give the title compound (2 g, 98% yield). MS (ESI) m/e 367 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.89 (s, 1H), 8.03 (s, 1H), 7.68 (d, J=8.5 Hz, 1H). 7.06 (d, J=2.0 Hz, 1H), 6.85-6.94 (m, 4H), 4.33 (t, J=6.6 Hz, 2H), 3.11 (s, 3H), 2.86 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:8][CH:7]=1)[CH:2]=[CH2:3].O.[NH2:21][NH2:22]>CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([C:10](=[N:21][NH2:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCc1ccc(C(=O)c2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: C=CCOCc1ccc(C(=NN)c2ccccc2)cc1
Yield: 20.7 %

Procedure:
To solution of 9 (1.09 g, 43 mmol) in methanol (10 ml) was added hydrazine hydrate (1.08 g 20 mmol). The mixture was heated to reflux for 48 h. then concentrated in vacuo. The residue was partioned between DCM and water and the organic layer collected and concentrated to yield 10 (1.10 g, 98%) as a mixture of cis and trans isomers and as a yellow oil; δH (CDCl3) 4.03, 4.13 (2×dt, 2H, J=1.4, 5.6 Hz, OCH2CH═CH2) 4.52, 4.60 (2×s, 2H, ArCH2O), 5.20, 5.27 (ddd, 1H, J=1.4, 3.0, 10.4 Hz, OCH2CH═CHH), 5.32, 5.37 (ddd, 1H, J=1.4, 3.2, 17.3 Hz, OCH2CH═CHH), 5.45 (bs, 2H, NNH2), 5.91-6.06 (m, 1H, OCH2CH═CH2), 7.28-7.31 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.46-7.55 (m, 5H, 2-, 2′-, 4′-, 6-, 6′-H) ppm; δC (CDCl3) 60.1, 71.5, 71.7 (ArCH2O, OCH2CH═CH2), 117.0, 117.3 (OCH2CH═CH2), 126.3, 126.4, 127.4, 128.0, 128.5, 128.7, 129.3 (Ar—C), 134.4, 134.6 (2×OCH2CH═CH2), 137.7, 138.1, 139.1 (Ar—C), 148.7 (C═N) ppm; νmax (thin film) 3404, 3289, 3057, 2855, 1612, 1444, 1411, 1277, 1083 cm−1; m/z (ES+) 267 ([M+H]+, 100%); found (EST+) 267.1492, C17H19N2O requires 267.1492.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12]([N:31]2C[CH2:34][C@@H:33]([OH:36])[CH2:32]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].Cl.OC1CNC1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:31]2[CH2:34][CH:33]([OH:36])[CH2:32]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl
Agent: OC1CNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
DIPEA (3.67 mL, 21.0 mmol) was added to (R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 2.77 g, 7.0 mmol) and 3-hydroxyazetidine HCl (0.920 g, 8.40 mmol) in iPrOH (7.0 mL) in a vial which was sealed and the RM mixture was stirred at 140° C. for 1.5 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow foam. HPLC (Condition 4) tR=5.37 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=432/434 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:17][C:18]#[N:19])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>CO.Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:17](=[N:20][OH:21])[C:18]#[N:19])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: N#CCc1nc2cnc(Br)cc2n1-c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#CC(=NO)c1nc2cnc(Br)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
The product from Step 5 (2.5 g, 7.99 mmol) in methanol (40 mL) and 2 N hydrochloric acid (16 mL) was treated portionwise with NaNO2 (1.10 g, 16 mmol) and allowed to stir at rt for 1 h. The resulting tan precipitate was filtered and washed with methanol to give the title compound (2.7 g, 99%). MS (ES+) m/e 342/344 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[C:4]([N+:12]([O-:14])=[O:13])[C:5](C)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:16](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: Cc1c(Br)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 104.6 %

Procedure:
To stirred solution of 5-bromo-2,4-dimethyl-3-nitrobenzoic acid (13 g, 47.44 mmol) in DMF (120 mL), sodium carbonate (15 g, 142.2 mmol) and methyl iodide (4.4 ml, 71.16 mmol) were added. Resulting reaction mass was heated at 60° C. for 8 h. On completion, water was added to the reaction mass and extraction was carried out using ethyl acetate. Combined organic layers were washed with sat. bicarbonate solution and 5 N HCl, dried over sodium sulphate, concentrated under reduced pressure giving desired compound (12.9 g, 86%).