Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>COCCO>[NH:10]([C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)[NH2:11]
Reactant: NN
Reactant: Oc1ccnc(O)c1
Solvent: COCCO
Solvent: O
Product: NNc1cc[nH]c(=O)c1
Reaction time: 24 h
Yield: 88.3 %

Procedure:
2,4-dihydroxypyridine (20.3 g, 183.0 mmol) was added to the mixture of 2-methoxyethanol (400 ml) and 55% solution of hydrazine hydrate (80 ml) at room temperature. The reaction mixture was refluxed under stirring for 24 hours and then concentrated under reduced pressure. The resulting residue was recrystallized with ethanol to give the titled compound as a white solid. (Yield: 88.3%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:18][CH:9]2[C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]3)=[CH:4][C:3]=1[CH3:19]>C1C=CC=CC=1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]2=[O:18])=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc(C23CC(C)(C)CC(C)(C)C2O3)ccc1F
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(C2CC(C)(C)CC(C)(C)C2=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a cooled solution (0° C.) of the epoxide from Example 1, Step A above (32.7 g, 125 mmol) in benzene (200 ml) is added dropwise 7.6 ml BF3 ·OEt2 (62 mmol). The cooling bath is removed and the reaction mixture warmed to room temperature and stirred for 2 hours. The benzene is removed under reduced pressure and provides a residue which is dissolved in ether (300 ml) and washed with saturated ammonium chloride. The ether layer is concentrated under reduced pressure to provide 26 g (80%) of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexanone. The ketone is recrystallized from pentane to give a white solid; m.p. 63°-64° C.: 1H NMR δ=1.05 (s,3), 1.1 (s,3), 1.3 (s,3), 1.32 (s,3), 1.75 (s,2), 2.0 (q,2), 2.3 (s,3), 3.95 (dd,1), 6.95 (m,3).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@@H:38]([N:42]1[C@H:47]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[C@@H:46]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=2)[CH2:45][C@@:44]([CH2:63][C:64]([OH:66])=[O:65])([CH3:62])[C:43]1=[O:67])[CH:39]1[CH2:41][CH2:40]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[Cl:61][C:57]1[CH:56]=[C:55]([C@@H:46]2[C@@H:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[N:42]([C@@H:38]([CH:39]3[CH2:40][CH2:41]3)[CH2:37][OH:36])[C:43](=[O:67])[C@:44]([CH2:63][C:64]([OH:66])=[O:65])([CH3:62])[CH2:45]2)[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of tetrabutylammonium fluoride, (1.0 M in THF, 0.453 mL, 0.453 mmol) was added to a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 251, Step E, 108 mg, 0.151 mmol) in THF (4 ml) and the reaction was stirred at ambient temperature for 20 hours. Analysis by LC-MS showed incomplete reaction so an extra 0.225 ml of tetrabutylammonium fluoride solution was added and the reaction was stirred for another 26 hours. The mixture was diluted in ethyl acetate then washed with water and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by RP-HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 10% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[C:20]1(S(N)(=O)=O)[CH:25]=CC=C[CH:21]=1.ClC1C=CC=CC=1C(Cl)=O.[H-].[Na+].C(Br)C=C>O1CCCC1>[CH2:25]([N:6]([C:4](=[O:5])[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:20]=[CH2:21]
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCN(C(=O)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
3.0 g (0.01 mole) of N-2-chlorobenzoyl benzenesulfonamide prepared from benzenesulfonamide and 2-chlorobenzoyl chloride was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry tetrahydrofuran. After stirring for 30 minutes at room temperature, 1.48 g (0.012 mole) of allyl bromide was added. Then the mixture was reacted for 2 hours under the same conditions. The tetrahydrofuran was distilled off under reduced pressure, and cold water was added. The resulting oil layer was extracted with benzene. The benzene layer was separated, dried over anhydrous magnesium sulfate, and concentrated to afford a white solid. Recrystallization from methanol afforded compound No. 27 in Table 2 in a yield of 35%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:35][CH:34]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(CO)cc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 28.5 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (50 mg, 0.10 mmols), [4-(hydroxymethyl)phenyl]boronic acid (50 mg, 0.30 mmols), cesium carbonate (200 mg), and Pd(PPh3)4 (5 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 29%)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([CH2:14][CH2:15][C:16]#[N:17])(C2C=NC=CN=2)[CH2:4][CH2:3]1.C1(N)CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]1[C@@H:16]([NH2:17])[C@@H:14]1[C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: N#CCCC1(c2cnccn2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CC(=O)O
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
A solution of 3-(4-oxo-1-(pyrazin-2-yl)cyclohexyl)propanenitrile (610 mg, 2.7 mmol, 1.0 equiv) in acetonitrile (10 mL) was treated with cyclopropylamine (380 μL, 5.3 mmol, 2.0 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (1.1 g, 5.3 mmol, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. Purification of the crude material by flash chromatography (SiO2, 70-80% EtOAc/hexanes containing 2.5% triethylamine) gave 0.24 g of the trans amine (0.89 mmol, 33%) and then further elution afforded 0.24 g of the cis amine (0.89 mmol, 33%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1>>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:2])=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 44.8 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 4-aminophenylacetate (61.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethoxycarbonylmethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (33.6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[N:26][N:25]=2)[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccc(OC)cc12
Reactant: Clc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
As in Example 132, 1-butyl-4-hydroxy-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (2.9 g) was reacted with 5-chloro-1-phenyl-1H-tetrazole (1.87 g) in dimethylformamide (25 mL) in the presence of potassium t-butoxide (1.25 g). After 0.5 hours at room temperature, the reaction was worked up in the described manner and the crude product was crystallized from diethyl ether-hexane to afford 2.9 g of 1-butyl-7-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester, mp 94°-96° C. A sample was recrystallized from the same solvents to provide the analytical specimen, mp 95.5°-96.5° C. Anal. Calcd for C25H26N4O4 : C, 67.25; H, 5.87; N, 12.55 Found: C, 67.16; H, 5.99; N, 12.66
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[S:20](Cl)(=[O:22])=[O:21])[CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([NH:8][S:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[N:10]=[CH:11][CH:12]=[CH:13]2)(=[O:21])=[O:22])[CH3:6]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
methyl-2-amino-2-methylpropanoate hydrochloride (5 g, 32.6 mmol) was dissolved in CH2Cl2 (110 ml), added with quinoline-8-sulfonyl chloride (8.18 g, 35.9 mmol) and triethylamine (18 ml, 130.6 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(quinoline-8-sulfonamido)propanoate (8.74 g, 32.8 mmol, 95%).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]1[O:49][C@@H:48]1[CH2:50]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:50][C@@H:48]4[CH2:47][O:49]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Reactant: OC[C@@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (110 mg, 0.30 mmol) in THF (9 mL), PPh3 (150 mg, 0.57 mmol) and (R)-glycidol (42 mg, 0.57 mmol) are added. The mixture is cooled to 0° C. before DEAD (248 mg, 0.57 mmol) is added. The mixture stirred for 1 h and is warmed to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (119 mg) as a yellow oil; LC-MS: tR=0.95 min; [M+1]+=423.21.
Reaction SMILES: C(OC[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:17]=[C:12]2[C:11]([C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1>[C:27]([C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:16]3[N:17]=[C:12]4[C:11]([C:30]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:37])=[CH:10][NH:9][C:13]4=[N:14][CH:15]=3)=[N:19][N:20]2[CH3:29])=[CH:25][CH:24]=1)#[N:28]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COC(=O)C(C)(C)C)c2ccc(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(C#N)cc21
Reaction time: 15 h
Yield: 13 %

Procedure:
To a stirred solution of (2-(6-cyano-1-methyl-1H-indazol-3-yl)-7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (45 mg, 0.089 mmol) in 2 mL of THF was added a solution of 10% NaOH (2 mL) at room temperature and the reaction mixture was stirred for 15 hours. The solvent was evaporated under reduced pressure. The residue was diluted with water and adjusted to pH 5-6. The mixture was filtered and the filter cake washed with DMSO (3 mL), MeOH (3 mL) and then dried to give 2-(6-cyano-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (4.5 mg, 12%) as white solid. MS: (M+H)+=390; 1H NMR (300 MHz, DMSO): δ 12.95 (brs, 1H), 9.14 (s, 1H), 8.79 (d, 1H, J=8.1 Hz), 8.54 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 5.15 (brs, 1H), 4.27 (s, 3H), 3.64 (d, 2H, J=5.4 Hz), 1.47 (s, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C>O1CCCC1>[CH3:1][S:2]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][Br:6])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Methanesulfonyl chloride (50 g, 436 mmol) was added to a solution of 2-bromo-1-(4-hydroxyphenyl)-ethan-1-one (85 g, 395 mmol) and triethylamine (48 g, 474 mmol in tetrahydrofuran (1000 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to afford 4-(2-bromoacetyl)phenyl methanesulfonate (96 g, 83%) as white crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:37].[Na+].[Na+]>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:19][CH:20]=4)[C:15](=[O:37])[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A solution of 9.0 g (0.019 mole) 2,7-bis(4-piperidinobutyryl)fluorene, 7.54 g (0.0253 mole) sodium dichromate and 300 ml of glacial acetic acid is stirred and refluxed for one hour. The reaction mixture is evaporated to semi-dryness and made basic using concentrated ammonium hydroxide. The solid which precipitates is filtered, washed with water and chromatographed on alumina using chloroform as the eluant. The solvent is removed from the fraction collected, leaving a solid residue which is recrystallized three times from chloroform-acetone to yield 2,7-bis(4-piperidinobutyryl)fluoren-9-one, M.P. 168°-170° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][CH2:33][CH2:34][CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCCC=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 92.8 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.52 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.64 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (452 mg) as yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)cc1
Yield: 116.5 %

Procedure:
A mixture of 2-bromo-1-(4-methoxyphenyl)ethanone (5.00 g, 21.8 mmol) and thiourea (1.72 g, 22.6 mmol) in 95% EtOH (40 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-methoxyphenyl)thiazol-2-amine (5.24 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, 2 H), 6.99 (s, 2 H), 6.92-6.91 (m, 2 H), 6.82 (s, 1 H), 3.76 (s, 3 H).
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]=[C:1]=[O:4])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](N=C=O)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tint=2-5° C. for 30 min, at which point HPLC analysis indicates >99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4% yield). 1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H). The material was used in Step 3 without further purification.
Reaction SMILES: CC(C)([O-:4])C.[K+].[I:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=1.O.Cl>ClCCl.C(COC)OC>[I:7][C:8]1[CH:9]=[CH:10][C:18]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]([OH:21])=[O:4])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2ccccc2-c2ccc(I)cc21
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(I)cc1
Temperature: 25 °C
Yield: 772 %

Procedure:
Add potassium tert-butoxide (5.61 g, 0.05 moles) and dimethoxyethane (67 mL) to a 250 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, and a nitrogen inlet. Stir the mixture at ambient temperature until the solid dissolves. Add 2-iodofluoren-9-one (1.5 grams, 0.005 moles, preparation 54) and stir until the solid dissolves. Add water (0.27 grams, 0.015 moles) and stir the reaction mixture at 23° C. for 1 hour. Add dichloromethane (70 mL) and concentrated hydrochloric acid to pH 1.0. Add water (50 mL) and separate the phases. Concentrate the organic phase under reduced pressure (15-25 mm) to a solid, and suspend the solid in a mixture of hexane (5 mL) and methyl-tert-butyl ether (5 mL) at ambient temperature for 3 hours. Isolate the solid by filtration and rinse the filter cake with pentane. Vacuum dry the solids to provide the title compound (1.25 grams, 0.0386 moles, 77.1% yield). 1H NMR (acetone-d6, 500.0 MHz): δ 7.94 (dd, 1H, J=1, 7.5); 7.82 (app. d, 2H, J=8); 7.66 (td, 1H, J=1, 7.5); 7.55 (td, 1H, J=1, 8); 7.44 (dd, 1H, J=1, 7.5); 7.22 (app. d, 2H, J=8).