Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[N:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C1C(=O)N([Br:29])C(=O)C1.ClCCl.[Cl-].[Na+].O>ClCCl>[Br:29][C:15]1[CH:14]=[CH:13][C:12]([N:4]([C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[CH3:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: Cc1ccccc1N(c1ccccc1)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1N(c1ccc(Br)cc1)c1ccccc1C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-N-phenyl-N-(o-tolyl)aniline (Compound 10) (8.2 g, 30 mmol) in dichloromethane (DCM) (100 mL), was added n-bromosuccinimide (NBS) (5.34 g, 30 mmol) at about 0° C. and stirred for about 4 hours. The resulting mixture was worked up with dichloromethane/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. The desired fraction was collected, and removal of solvent gave a white solid (Compound 11) (10.7 g, in 100% yield).
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]2[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:7]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 3.4 %

Procedure:
To a solution of 9-(2-azido-2-(pyridin-4-yl)ethyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800 mg, 2.3 mmol) in ethanol-water (9 mL: 1 mL) were added zinc dust (600 mg, 9.2 mmol) and ammonium chloride (490 mg, 9.2 mmol) and the reaction mixture stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyridin-4-yl)ethanamine (25 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (s, 2H), 7.62 (bs, 2H), 7.23 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.9 (m, 1H), 4.8-4.58 (m, 3H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.6-3.4 (m, 2H), 3.1 (bs, 4H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([C:15](OCC)=[O:16])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[BH4-].[Li+].O>C(O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([CH2:15][OH:16])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: CCOC(=O)C1NCCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c21
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)C(CO)NCC3
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a stirred solution of the product of step D (51 mg, 0.12 mmol) in ethanol (5 mL) was added lithium borohydride (44 mg, 2.00 mmol) at ambient temperature. After 3 h, water (2 mL) was added and the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate to ethyl acetate) to afford (6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-1-yl)methanol (30 mg, 64%) as a brown oil: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.94 (m, 3H), 7.82 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 4.23 (dd, J=4.0, 2.0 Hz, 1H), 3.95 (dd, J=11.2, 4.0 Hz, 1H), 3.77 (dd, J=10.8, 7.8 Hz, 1H), 3.31-3.17 (m, 2H), 2.84-2.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (0.4 g, 2.0 mmol), 3-chlorophenyl boronic acid (0.62 g, 4.0 mmol), [RhCl(cod)]2 (49 mg, 0.10 mmol) and TEA (0.42 ml, 3.0 mmol) in water (6 ml) and 1,4-dioxane (1 ml) was stirred at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-propionic acid methyl ester XL (90 mg, 62% yield) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:18][C:19]1[C:27]([Br:28])=[CH:26][C:25]([Br:29])=[CH:24][C:20]=1[C:21](O)=[O:22].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:29][C:25]1[CH:26]=[C:27]([Br:28])[C:19]2[N:18]=[C:15]([C:4]3[N:5]([C:7]4[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:17][C:21](=[O:22])[C:20]=2[CH:24]=1
Reactant: N#Cc1cccnc1-n1cc(Br)cc1C(=O)O
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: N#Cc1cccnc1-n1cc(Br)cc1-c1nc2c(Br)cc(Br)cc2c(=O)o1

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-cyano-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-cyano-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:12])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)NCc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 0.98 mmol) and 1,1'-carbonyldiimidazole (206 mg, 1.27 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.64 mL, 5.88 mmol) is added and stirring is continued at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:2) provides 5-chloro-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=80°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Reactant: OCCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and 2-phenylethanol (Aldrich), the title compound was prepared as a solid (mp=154.0-155.2° C.). The reaction was monitored by tlc (Rf=0.15 in 15% EtOAc/hexanes) and the product was purified by flash chromotography using 15% EtOAc/hexanes as the eluent.
Reaction SMILES: CN(C=O)C.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([CH2:27][C@@H:28]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:29][CH2:30]2)[CH2:25][C@H:24]3[OH:45])[CH2:21][CH2:20]1)[CH3:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:45][C@@H:24]1[CH2:25][C@@H:26]2[C@:31]([CH3:32])([CH2:30][CH2:29][C@H:28]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH2:27]2)[C@@H:33]2[C@@H:23]1[C@H:22]1[C@:36]([CH3:37])([CH2:35][CH2:34]2)[C@@H:19]([C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:20][CH2:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 400 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A flame-dried round-bottom flask with stirring bar was charged with sodium hydride (60% in mineral oil, 28 mg, 0.69 mmol), equipped with a septum and a gas-needle inlet and flushed with argon. The mineral oil was removed by washing (3×) with dry pentane, and the pentane was removed to provide the sodium hydride as a powder. Dry DMF (2.0 ml) was added. A solution of alcohol 2006 (40 mg, 0.069 mmol) in dry THF (2 ml) was added dropwise via syringe. The reaction mixture was stirred overnight and then heated to 400° C. in an oil bath over a 20-minute period. Freshly distilled benzyl bromide (0.165 ml, 1.38 mmol) was added dropwise, and the reaction mixture was stirred at 400° C. for 10 hours. The reaction was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The flask was placed under vacuum overnight to remove any residual DMF. The crude material was purified by flash chromatography (SiO2, hexanes:EtOAc 50:1) giving compound 2007 as a white solid (40 mg, 0.060 mmol, 87%). A gradient of increasing EtOAc concentration provided other components, including the 7α-formate (1 mg, 1%) as well as recovered starting material (3 mg, 8%). Compound 2007:=1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5 H, benzyl Ar-CH2), 4.73-4.66 (m, 1 H, methine H), 4.535 (d, J=12.0 Hz, 1/2 H, benzyl-CH2) , 4.53 (d, J=12.0 Hz, 1/2 H, benzyl-CH2), 4.26 (d, J=12.2 Hz, 1/2 H, benzyl-CH2), 4.245 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 3.95-3.85 (m, 1 H, THP CH2O), 3.66-3.52 (m, 3 H, THP CH2O & C-24 H), 3.50-3.45 (m, 1 H, C-3 H), 1.08 (s, 3 H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3 H, C-18 H), 0.04 (s, 6 H, TBDMS CH3); MS (CI/isobutane) m/z 668 (M+1, 6%), 584 (M+1-THP, 18%), 475 (M+1-THPOH, 30%), 457 (M+1-THPOH-HOBn, 58%), 343 (M+1-THP-HOBn-TBDMSOH, 100%), 325 (M+1-THPOH-TBDMSOH-HOBn, 83%).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21]([O:25]CC)(=O)[CH:22]=[O:23]>C1COCC1>[CH2:2]([C:22]([OH:23])([CH:21]([OH:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)C=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (360 mg, 14.6 mmol) and a stir bar. The flask was dried with a heat gun for 5 minutes then cooled under nitrogen. The flask was charged with THF (5 mL) and a small grain of iodine. A solution of linoleyl bromide (4 g, 12.1 mmol) in THF (5 mL) was added slowly and after 5 minutes the reaction initiated vigorously. The solution was stirred at room temperature for 2 hours, and then ethyl glyoxalate (0.5 mL, 2.42 mmol, 50% solution in toluene) was added. The exothermic reaction was finished immediately and quenched with saturated ammonium chloride solution (5 mL). The solution diluted with water and extracted with diethyl ether (3×50 mL). The combined diethyl ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel 60 (eluted with 100% Hexanes to 15% Et2O in hexanes) to afford (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol as a colorless oil (945 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[O:19]C)[N:3]=1.NC1N=C(N)N=[C:24]([C:29]2[CH:38]=[CH:37][C:36]3C(=CC=CC=3)[C:30]=2[O:39]CC2C=CC=CC=2)[N:23]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:30](=[O:39])[C:29]2[CH:38]=[CH:37][CH:36]=[N:23][CH:24]=2)[N:5]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:19])[N:3]=1
Reactant: COc1c(-c2nc(N)nc(N)n2)ccc2ccccc12
Reactant: Nc1nc(N)nc(-c2ccc3ccccc3c2OCc2ccccc2)n1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccc3ccccc3c2O)n1

Procedure:
The same methods as in the preceding examples were conducted using 2,4-diamino-6-(1-methoxy-2-naphthyl)-s-triazine or 2,4-diamino-6-(1-benzyloxy-2-naphthyl)-s-triazine to afford 2-amino-4-nicotinamido-6-(1-hydroxy-2-naphthyl)-s-triazine, pale yellow needles, melting point 301° to 302° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@H:22]([C@@H:27]4[O:31]C(C)(C)O[C:28]4=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:27]([OH:31])[C:28]([NH:36][OH:37])=[O:34])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of (5S)-5-((1S)-1-{[(2R)-4-(4′-fluorobiphenyl-4-yl)-2-methylpiperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (230 mg, 0.48 mmol, 1.0 eq) in a mixture of iPrOH (4 mL) and THF (4 mL) was added a 50% aq. solution hydroxylamine (0.08 mL, 1.43 mmol, 3.0 eq). The reaction mixture was stirred at rt for 8 h. Evaporation of the solvent gave a white solid. This product was washed with iPr2O (2×), filtered and dried under vacuum to give the title compound as a white powder (89%). M−(EST): 456.3; M+(ESI): 458.4. HPLC (Condition A), Rt: 3.9 min (HPLC purity: 97.5%).
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](CCC(O)=O)=[CH:46]1>>[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:46]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(1H-indol-3-yl)-propionic acid (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:39])=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[C:22]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:30])=[CH:28][C:21]=3[N:20]=2)[CH:17]=1>CC#N.C(Cl)Cl>[Cl:39][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:17][C:16]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])=[CH:28][C:21]=2[N:20]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CC#N
Product: Cn1c(Nc2cc(CNS(=O)(=O)c3cccs3)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21

Procedure:
Thiophene-2-sulfonyl chloride (64 mg, 0.35 mmol) in MeCN (1 mL) was added to a mixture of 2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide (150 mg, 0.35 mmol), TEA (150 L, 1.1 mmol) and MeCN (2 mL). After 12 h at rt the mixture was diluted with DCM and washed with NH3 (aq, sat) and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound. Yield: 36 mg (18%). 200 MHz 1H-NMR (DMSO-d6, ppm) 8.50-8.36 (2H, m) 8.35-8.22 (1H, m) 7.94-7.82 (3H, m) 7.69-7.57 (2H, m) 7.42 (1H, d, J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.18-7.11 (1H, m) 7.04-6.95 (1H, m) 4.09-3.96 (2H, m) 3.71 (3H, s) 3.14-3.00 (2H, m) 1.77-1.47 (7H, m) 1.29-1.07 (4H, m). MS m/z: 572 [M+H]+.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][C:12]2[C:13]([C:20](O)=[O:21])=[CH:14][N:15]([CH3:19])[C:16](=[O:18])[CH:17]=2)=[C:9]([F:25])[CH:8]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[Br:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][C:12]2[C:13]([C:20]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:21])=[CH:14][N:15]([CH3:19])[C:16](=[O:18])[CH:17]=2)=[C:9]([F:25])[CH:8]=1
Reactant: NOCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 38 %

Procedure:
2-(Aminooxy)ethanol, 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and DMT-MM were reacted in MeOH as outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) gave 4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (38%); m.p. (EtOAc/Hexane) 124-128° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1H), 9.50 (br s, 1H), 8.13 (s, 1H), 7.69-7.65 (m, 1H), 7.47-7.41 (m, 2H), 5.53 (d, J=0.7 Hz, 1H), 4.78 (s, 1H), 3.91 (t, J=5.0 Hz, 2H), 3.61 (t, J=5.0 Hz, 2H), 3.36 (s, 3H). LCMS (ACPI−) 400 (80%), 398 (100%). Anal. Calcd for C15H15BrFN3O4.0.25 H2O: C, 44.5; H, 3.9; N, 10.4. Found C, 44.3; H, 3.5; N, 10.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][CH2:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:21]([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:15][CH2:16]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1NCCC2
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: CN1CCCc2cccc(NC(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred solution of 8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.876 g, 3.52 mmol) in CH2Cl2 (35 mL), at room temperature was added excess methyl iodide (2 mL, 32.12 mmol). The mixture was stirred at room temperature for 48 hours. The mixture was poured into saturated aqueous NaHCO3 (25 mL) and diluted with CH2Cl2 (25 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by flash chromatography (36 g silica gel, 10:1 hexanes-ethyl acetate) provided 0.83 g (90%) of 1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline as a colorless oil. 1H NMR (CDCl3) δ 1.53 (s, 9H), 1.84-1.92 (m, 2H), 2.62 (s, 3H), 2.79 (t, 2H, J=6.6 Hz), 3.03-3.07 (m, 2H), 6.73 (d, 1H, J=7.8 Hz), 6.95 (dd, 1H, J=7.8, 7.8 Hz), 7.18 (br s, 1H, NH), 7.82 (br d, 1H, J=7.8 Hz).
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][NH:4][CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][N:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3
Reactant: O=c1cccc2n1C[C@@H]1CNC[C@H]2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=c1cccc2n1C[C@H]1C[C@@H]2CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a 25 ml round bottom flask was added 0.510 gm (2.68 mmol) cytisine in 10 ml of 1,2-dichloroethane. The above solution was treated with 0.272 ml (2.68 mmol) benzaldehyde, 153 μl acetic acid and 0.852 gm (4.02 mmol) sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 hours and was then partitioned between methylene chloride and 1 N HCl (aq). The organic phase was washed with brine, dried and the solvent evaporated in vacuo to a solid. Chromatography on silica gel eluting with 1% methanol in methylene chloride afforded 434 mg (58%) of the title product which was used in the next step. 1H NMR (CDCl3, 250 MHz) δ 7.28 (dd, 1H), 7.15 (m, 3H), 6.98 (m, 2H), 6.98 (m, 2H), 6.52 (d, 1H), 5.92 (d, 1H), 4.10 (d, 1H), 3.88 (dd, 1H), 3.40 (dd, 2H), 2.88 (m, 3H), 2.39 (br.s, 1H), 2.3 (dd, 2H), 1.82 (dd, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][C@@H:18]([NH:27][C:7]1[C:6]([F:9])=[CH:5][C:4]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:3][C:2]=1[F:1])[CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NS(=O)(=O)c1cc(F)c(F)c(F)c1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1c(F)cc(S(N)(=O)=O)cc1F

Procedure:
The title compound was prepared from 3,4,5-trifluorobenzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.