Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC([O-])=O.[Na+].[NH2:42][OH:43].Cl>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:42][OH:43])[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1cccc(F)c1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=NO)c1cccc(F)c1F
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of 1-(2,3-difluorophenyl)-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (21.1 g, 0.0435 mol, 1.0 equiv.) in MeOH (106 mL) was added NaOAc (5.36 g, 0.0653 mol, 1.50 equiv.) at ambient temperature. After 5 min., NH2OH HCl (3.33 g, 0.048 mol, 1.10 equiv.) was added in portions. The suspension was warmed to 35° C. and stirred for 1 h. The reaction mixture was cooled to 17.8° C. and stirred for 15 mins, then filtered and rinsed with EtOAc (84 mL). The filtrates were concentrated under vacuum (T<30° C.). To the resulting residue was charged 2-methoxy-2-methylpropane (169 mL) and water (21.1 mL). The organics were washed with sat. aq. NaHCO3 (53 mL) and 18% aq. NaCl (21 mL). The organics were concentrated under vacuum to afford the title compound as an oil (21.0 g). 1H NMR (500 MHz, CDCl3) δ ppm 7.42-7.32 (m, 6H), 7.30-7.15 (m, 10H), 7.16-7.06 (m, 1H), 7.03-6.95 (m, 1H), 5.72-5.58 (m, 1H), 5.24-5.13 (m, 2H), 4.80 (d, J=14.6 Hz, 1H), 4.73 (d, J=14.6 Hz, 1H), 4.45 (d, J=12.4 Hz, 0.3H), 4.35 (d, J=12.4 Hz, 0.3H), 3.99-3.91 (m, 0.3H), 3.91-3.83 (m, 1H), 3.20 (dd, J=9.9, 6.8 Hz, 0.3H), 3.09 (dd, J=9.8, 6.6 Hz, 1H), 3.02 (dd, J=9.9, 4.2 Hz, 0.3H), 2.95 (dd, J=9.8, 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 155.40, 150.59 (dd, JCF=248.1, 13.0 Hz), 148.86 (dd, JCF=252.6, 13.5 Hz), 143.96, 135.10, 128.73, 128.69, 127.72, 127.68, 126.92, 126.85, 124.96, 124.56 (d, JCF=10.6 Hz), 124.03-123.86 (m), 118.64 (d, JCF=15.1 Hz), 117.92 (d, JCF=17.2 Hz), 86.66, 86.50, 81.30, 80.32, 69.20, 66.54, 66.48, 62.57.
Reaction SMILES: [CH2:1]([S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:21](=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>C(O)C>[CH2:1]([S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]=[CH:21][C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSc1ccccc1N
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CCCCCCCCCCCCSc1ccccc1N=Cc1ccccc1O
Yield: 97 %

Procedure:
Into a 1-liter flask equipped with condenser, stirrer and thermometer, were placed 220 g (0.75 tool of 2-(dodecylthio)aniline, 200 g of ethanol, and 91.5 g (0.75 mol) of salicylaldehyde. The resultant solution was heated at reflux overnight. Upon cooling, solvent was removed at reduced pressure to afford 290 g (97%) of product as a dark yellow/brown oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:39][NH:40][CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:40]([CH3:39])[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCC1
Reactant: CNCc1ccc2ccccc2c1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2ccccc2c1)C(=O)/C=C/c1cnc(N)c(CN2CCCC2)c1
Yield: 57 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-pyrrolidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-naphthalen-2-ylmethyl-amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (51 mg, 57%) was prepared as a light, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.36-8.25 (m, 2H), 7.52-6.98 (m, 4H), 6.40-6.15 (m, 1H), 5.05-4.84 (m, 2H), 4.20 (s, 2H), 3.74-3.67 (m, 3H), 3.58-5.30 (m, 8H), 3.10-2.73 (m, 6H); MS (ESI) m/e 401 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([O:10]CC)=[O:9])[CH:6]=1.CO.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: CCOC(=O)Cn1cc(C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 0.51 g (3.0 mmol) of ethyl [4-methyl-1H-1,2,3-triazole-1-yl]acetate from step B above in tetrahydrofuran (10 ml), methanol (6 ml) was added 6 mL (6 mmol) of an aqueous 1.0 M lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 8 mL of a 2 N hydrochloric acid solution which was then evaporated to remove all volatiles. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a white solid (0.40 g, 95%). LC/MS 142 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]1)=[O:15].[H-].[Na+].Br[CH2:45][CH2:46][O:47][CH3:48]>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH3:48][O:47][CH2:46][CH2:45][O:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:18]1)=[O:15]
Reactant: COCCBr
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (215 mg) was dissolved in DMF (3 ml), sodium hydride (50% in oil, 30 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, 1-bromo-2-methoxyethane (55 μl) was added under ice-cooling, and the mixture was further stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (149 mg).
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:18]([F:21])([F:20])[F:19])[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=O)C.S([O-])(O)(=O)=O.[K+].C(OCC)(=O)C>[OH-].[NH4+].O.CO.C(O)(=O)C.CCCCCC>[F:19][C:18]([F:20])([F:21])[CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CC(=O)SCC(C(=O)N[C@@H](CC(C)C)C(=O)O)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)C(CS)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A suspension of the product of Example 18 (2.3 g., 6.98 mmol.) in 4.45 mL of concentrated ammonium hydroxide and 10 mL of water was stirred at room temperature under argon for 8 minutes. The resulting clear solution was acidified with 5% potassium hydrogen sulfate solution to pH 2 and extracted with 100 mL of ethyl acetate followed by 3×75 mL of additional extractions. The combined ethyl acetate extract was washed with 100 mL of brine, dried (MgSO4) and evaporated to give 1.94 g. of an off-white solid. Flash chromatography on 200 g. of silica gel eluting with ethyl acetate: hexanes:acetic acid, 100:100:1 afforded 1.72 g. of the title isomer A product as a white crystalline solid, m.p. 143°-145° C., TLC Rf =0.38 (100:50:1 ethyl acetate:hexane:acetic acid), [α]D =-62.2° (c=1.00, methanol).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:22].[O:23]1[C:27]2([CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH:30]2[CH2:31][CH2:32][C:27]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:28][CH2:29]2)[CH2:18][C:17]1=[O:22]
Reactant: CN1CCNCC1=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1=O

Procedure:
26.18 g Sodium triacetoxyborohydride are added at 5° C. to a solution of 10.0 g 4-methyl-3-oxo-piperazine, 13.51 g 1,4-dioxa-spiro[4,5]decan-8-one, 5.65 ml acetic acid and 200 ml dichloromethane. After 23 hours stirring at ambient temperature 100 ml dichloromethane and 100 ml 4N sodium hydroxide solution are added. The phases are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[N:25]=1.[CH:48]1([NH:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][C:58](B3OC(C)(C)C(C)(C)O3)=[C:57]([F:70])[CH:56]=2)=[O:53])[CH2:50][CH2:49]1>>[CH:48]1([NH:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([C:24]3[N:25]=[C:26]([C:37]4[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=4[S:44]([CH3:47])(=[O:46])=[O:45])[CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[N:29]=3)=[C:57]([F:70])[CH:56]=2)=[O:53])[CH2:50][CH2:49]1
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NC3CC3)cc2F)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 11). Material was purified by prep HPLC (low pH) to afford a brown gum, (70 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]2[CH2:17][C:18]([CH2:20][CH:13]1[CH2:14][CH2:15]2)=O.P(=O)(O)(O)O.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH2:17][CH:16]4[N:12]([CH3:11])[CH:13]([CH2:14][CH2:15]4)[CH:20]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CN1C2CCC1CC(=O)C2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1C2C=C(c3c[nH]c4cc(F)ccc34)CC1CC2
Temperature: 62.5 °C
Yield: 9.4 %

Procedure:
A solution of 2.0 gm (14.8 mMol) 6-fluoroindole in 50 mL acetic acid was heated to 55° C. and vigorously deoxygen-ated with nitrogen. To this reaction mixture were then added 4.12 gm (29.6 mMol) tropinone and 12.3 mL 2N phosphor-ic acid. The resulting mixture was heated at 60-65° C. for 24 hours. The reaction mixture was cooled to room temperature and then poured into ice containing about 300 mL acetic acid. The pH of this mixture was then adjusted to about 8 by the addition of 50% aqueous NaOH. The resulting mixture was extracted well with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichlorometh-ane containing 30% dichloromethane saturated with ammonia and from 1-15% methanol. Fractions containing product were combined and concentrated under reduced pressure. The solid residue was crystallized from ethanol to provide 0.358 gm (9.44%) of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:36]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[CH:37]=2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 5, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and 2-chloropyridine-4-boronic acid. The desired product was obtained in a yield of 7% as white solid. MS (m/e): 609.0 (M+H, 100%).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1>C(OCC)C.[Ag]=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([O:18][CH2:1][CH2:2][CH3:3])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Reactant: CCCI
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Temperature: 50 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
0.22 ml (2.31 mmol) of propyl iodide is added to a mixture of 793 mg (3.48 mmol) of silver oxide and 300 mg (1.16 mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 3 ml of diethyl ether. The reaction mixture is stirred at 50° C. for 12 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 291 mg of methyl (S)-3-(4-bromophenyl)-2-(propyloxy)propanoate are obtained in the form of an oil. Yield=83%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=O)C>CO>[O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Solvent: CO
Product: COC(=O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Mercaptophenylacetic acid was prepared by a method described in the chemical literature (see D. Papa et al, J.Org. Chem., 1949, 24, 723, R. H. Glauert and F. G. Mann, J.Chem. Soc., 1952, 2127 and references therein). 2-Mercaptophenylacetic acid (1.68 g) was added to a stirred solution of sodium hydroxide (0.8 g) in methanol (10 ml), (compare D. C. Atkinson et al, J.Med. Chem., 1983, 26, 1361). The resulting orange solution was stirred at room temperature for 90 minutes then concentrated under reduced pressure, removing the final residues of methanol by azeotroping with toluene, to leave a yellow solid. Cuprous chloride (0.2 g) and a solution of 3-phenoxybromobenzene (2.49 g, prepared from 3-phenoxyphenol and triphenylphosphine dibromide by the method described by J. P. Schaefer et al, Org.Synth., Coll. Vol.5, 142) in DMF (10 ml) were added successively to a stirred solution of this yellow solid in DMF (20 ml). The resulting mixture was heated at 95° C. for 13/4 hours at 125° C. for 2 hours, and then at reflux for a further 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide then washed with ether (×3). The aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (×3). These extracts were washed with water, dried and concentrated to give a purple oil (2.2 g) consisting mainly of 2-(3-phenoxyphenylthio)phenylacetic acid. A solution of this oil in methanol (20 ml) was added to acidic methanol [prepared by carefully treating methanol (30 ml) with acetyl chloride (3.5 and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic layer was separated and washed successively with aqueous sodium hydroxide (×2) and water (×3) then dried and concentrated to give crude methyl 2-(3-phenoxyphenylthio)phenylacetate (2.06 g) as a purple oil.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.C(Cl)Cl>[Br:14][CH2:15][CH2:16][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[O:3][CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCBr
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of the potassium salt of 2-methoxy-4-nitrophenol (2.07 g, 10.0 mmol), 1,2-dibromoethane (1.72 mL, 20.0 mol), 1 N KOH (50 mL), tetrabutyl ammonium bromide (3.22 g 10.0 mol), and CH2Cl2 was stirred overnight. The reaction was diluted with 300 mL of EtOAc, washed with sat. NH4Cl solution (2×50 mL). The organic layer was dried over Na2SO4 prior to concentration in vacuum to a yellow solid. The solid was then washed with MeOH (2×5 mL) to yield 2.0 g (72%) of the title compound as a white solid. MS (ESI) 276, 278 (M+H)+.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[N:25]([CH3:26])[N:24]=[CH:23][C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:38]([O:37][C@@H:9]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[N:25]([CH3:26])[N:24]=[CH:23][C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[CH2:8][OH:7])([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl)benzo[d]thiazol-6-yl)ethyl pivalate: (68 mg, 0.115 mmol) in THF/CH3OH (1.5 mL/1.5 mL) was added 2N NaOH (0.57 mL, 1.15 mmol). The reaction mixture was heated at 45° C. for 2 h and cooled to rt. The reaction solution is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic solution is washed with water, brine, dried and concentrated to give crude product which was carried to next reaction without further purification. LCMS-ESI+: calc'd for C27H27ClN4O2S: 507.16 (M+H+); Found: 507.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[C:7]([Br:21])[CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.Cl.N1C=CC=CC=1>[Br:21][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:22]([CH2:23][CH2:24][CH3:25])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2cc(Br)ccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
A solution of tert-butyl N′-(3-amino-7-bromoquinolin-4-yl)hydrazinecarboxylate (37.1 g, 105 mmol) in 315 mL of toluene was treated with trimethyl orthobutyrate (16.7 mL, 105 mmol) and pyridine hydrochloride (0.12 g, 1.05 mmol). The reaction mixture was heated to reflux under an atmosphere of nitrogen. After 4 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 300 mL of CHCl3. The solution was washed with 5% Na2CO3 (100 mL), water (100 mL) and brine (100 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown foam. The foam was purified by chromatography (SiO2, 100:0 gradient to 95:5 CHCl3:MeOH) to yield 30.1 g of tert-butyl (7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate as a light brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4ccccc4)no3)CC2)cc1
Yield: 54.5 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (20 mg, 0.10 mmol) and 1-benylpiperazine (17.4, 0.10 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (64 mg, 0.30 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.1 hr and followed the same processes as in Example 1 to obtain 19.7 mg (54.5%) of the target compound.