Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O.O>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:9]=1
Reactant: COCCOCCBr
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Ex-29C: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., 1-bromo-2-(2-methoxyethoxy)ethane (0.24 g, 1.3 mmol) was added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1×15 mL), water (1×15 mL), and brine (1×15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74 m, 2H), 3.59 (m, 2H), 3.40 (s, 3H). HRMS (EI) Calcd. for C17H20O5S: 336.1031. Found: 336.1027.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([OH:24])[C@@H:12]1[OH:25])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[Cl-].[Mg+2].[Cl-].C(N(CCCC)CCCC)CCC>CN(C)C=O>[CH:22]1[C:20](=[O:21])[NH:19][C:17](=[O:18])[N:16]([C@@H:14]2[O:15][C@H:11]([CH2:10][O:9][P:1]([O:4][P:5]([O:8][P:1]([OH:4])([OH:3])=[O:2])([OH:7])=[O:6])([OH:2])=[O:3])[C@@H:12]([OH:25])[C@H:13]2[OH:24])[CH:23]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.5 %

Procedure:
A 0.154 M dimethylformamide solution of uridine 5′-diphosphate (UDP) tributylamine salt (584 μL, 90.0 μmol) and a 0.45 M dimethylformamide solution of anhydrous magnesium chloride (200 μL, 90.0 μmol) were added to a 0.15 M dimethylformamide solution of cUTP tributylamine salt (500 μL, 75.0 μmol), and the mixture was stirred at room temperature for 72 hours. The resultant reaction mixture was analyzed through HPLC (262 nm). As a result, Up5U (i.e., target product) was found to be produced from UTP at a synthesis yield of 50.5%.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:6]([C:5]([C:4](=[O:9])[CH3:3])([CH2:12][CH2:11][C:10]#[N:13])[CH2:12][CH2:11][C:10]#[N:13])(=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C(CCC#N)(CCC#N)C(C)=O

Procedure:
After addition of 0.25 g of KOH, dissolved in 2.5 ml of methanol, to 15.0 g of 2,4-pentandione, 35.0 g of acrylonitrile was added dropwise with the reaction temperature not exceeding 40° C. The product which was precipitated during the process was filtered off, washed with a small amount of acetone, and dried. Melting point: 185–186° C. Purity>98%. The product was colorless.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:36](=O)[N:37]([CH2:39][CH2:40][NH2:41])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:41][CH2:40][CH2:39][NH:37][CH3:36])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:22]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(F)cc2)cc1OC
Reaction time: 8 h
Yield: 79.1 %

Procedure:
N-(3,4-Dimethoxy-phenyl)-4-fluoro-benzenesulfonamide (0.51 g, 1.61 mM) was added to a solution of benzyl bromide (0.57 g, 4.82 mM) and potassium carbonate (0.66 g, 4.82 mM)in anhyrous acetone(10 ml). The reaction was stirred overnight. The undissolved solids were removed by filtration and the mother liquor was concentrated. This gum was triturated with hexanes to afford 0.52 g of the desired product as an off-white solid. H1 NMR(CDCl3) δ 3.66(s, 3H), 3.81(s, 3H), 6.42(m, 2H), 6.66(d, 1H, J=8.70 Hz), 7.23(m, 7H), 7.71(m, 2H). MS(ES) m/z 401.9; (MH+); HRMS for C21H20SFNO4: 401.1094.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH:15]([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CC(C)N
Solvent: CCCCCC
Product: CC(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In an argon atmosphere, 5.70 g (24.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 40 mL of hexane and after adding 2.90 g (49.1 mmol) of isopropylamine, the mixture was stirred at room temperature for 5 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.7×102 Pa) to obtain 1,3-di-tert-butyl-2-isopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHiPr) as a pale yellow liquid (yielded amount: 5.65 g, yield: 90%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([NH:9][C:10](=[O:22])[CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)[CH:8]=1.B(Br)(Br)Br.C(OCC)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([NH:9][C:10](=[O:22])[CH2:11][C:12]23[CH2:21][CH:16]4[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]4)[CH2:19]2)[CH2:13]3)[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(O)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(5-methoxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide prepared as described in Example 5 (1.00 g) in dichloromethane (20 ml), was added boron tribromide (4 ml of a 1.0M solution in dichloromethane) at −78° C. under an inert atmosphere. The reaction mixture was stirred for 24 hours and then warmed to ambient temperature and washed with brine. The organic layer was dried over magnesium sulphate (MgSO4) and concentrated under reduced pressure to yield a residue. Trituration with diethyl ether gave a solid (0.335 g). A portion of this material (0.050 g) was further purified by Supercritical Fluid chromatography using a Cyano column, eluting with a gradient of methanol in supercritical carbon dioxide to give the title compound as a white solid (0.030 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1.[C:29](=O)([O:32]C)[O:30][CH3:31]>C1COCC1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([O:30][CH3:31])=[O:32])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(C)ccn1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1ccnc(OC)c1
Reaction time: 0.5 h

Procedure:
To the solution of lithium diisopropylamide (Aldrich, 2.0M, 122 mL, 244 mmol), THF (90 mL) and hexamethylphosphoric triamide (Aldrich, 16 mL, 89 mmol) at −78° C. under nitrogen was added, in 10 min, a solution of 2-methoxy-4-methylpyridine (10.0 g, 81 mmol) in THF (30 mL). After 30 min, a solution of dimethyl carbonate (Aldrich, 7.5 mL, 90 mmol) in THF (30 mL) was added over 15 min. The stirring was continued for 2 h at −78° C. before the reaction was quenched with MeOH (30 mL). The mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude product was purified by silica gel chromatography. MS: 182 (M+1).
Reaction SMILES: CS(CC1C(C2C=CC=CC=2)=NC2C(C=1C(N[C@H](C1C=CC=CC=1)CC)=O)=CC=CC=2)=[O:3].[CH:33]([S:36][CH2:37][C:38]1[C:39]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[N:40][C:41]2[C:46]([C:47]=1[C:48]([NH:50][C@H:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][CH3:53])=[O:49])=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:35])[CH3:34]>>[CH:33]([S:36]([CH2:37][C:38]1[C:39]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[N:40][C:41]2[C:46]([C:47]=1[C:48]([NH:50][C@H:51]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:52][CH3:53])=[O:49])=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:3])([CH3:34])[CH3:35]
Reactant: CC[C@H](NC(=O)c1c(CSC(C)C)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CC[C@H](NC(=O)c1c(CS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Product: CC[C@H](NC(=O)c1c(CS(=O)C(C)C)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
This compound [two diastereomers] was prepared similarly to 3-[(methylsulfinyl)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (2, scheme 1) except 3-[(isopropylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (Example 13) was used instead of 3-[(methylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (1). 1H NMR (300 MHz, CDCl3) δ 8.90-8.68 (m, 1H), 8.16-8.03 (m, 2H), 7.80-7.27 (m, 12H), 5.35-5.12 (m, 1H), 4.30-3.67 (m, 2H), 2.86-1.83 (m, 3H), 1.19-0.55 (m, 9H); HRMS m/z 471.2077, calcd 471.2106.
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2sccc12

Procedure:
4-hydroxythieno[2,3-d]pyrimidine (300 mg, 2.0 mmol) in phosphorous oxychloride (1.5 ml) was heated to reflux for 1 hour. 4-chlorothieno[2,3-d]pyrimidine obtained by distilling off the solvent under reduced pressure. Without further purification of 4-chlorothieno[2,3-d]pyrinidine the resultant mixture was heated to reflux with 2-aminoindane (1.1 g, 8.0 mmol) in dry ethanol (6 ml) under an argon atmosphere for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane:ethyl acetate=5:2) to obtain the title compound (150 mg, 0.56 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH:30]([CH3:39])[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>C(#N)C>[CH3:39][C:30]1[N:7]2[CH:6]=[C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:4]=[CH:3][C:2]2=[N:1][C:31]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cn12
Temperature: 80 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
0.05 g (0.13 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide prepared according to the protocol described in step 4.2, 0.056 g (0.26 mmol) of 2-bromo-1-phenylpropan-1-one and 4 mL of acetonitrile are introduced into a 10 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is heated at 80° C. with stirring for 24 hours. After this time and cooling to room temperature, the precipitate obtained is filtered off and rinsed successively with 2 mL of acetonitrile and 2 mL of isopropyl ether. The solid obtained is dried under reduced pressure. 0.024 g of the expected product is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C[Si](Cl)(C)C.[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:41](=[O:42])[NH:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: O=C=Nc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)Nc2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 14 %

Procedure:
A solution of 8a (0.06 g, 0.14 mmol), trimethylsilyl chloride (0.01 mL, 0.08 mmol) and phenylisocyanate (0.1 mL, 0.92 mmol) in CH2Cl2 was stirred at room temperature for 5 days. The reaction mixture was then washed with saturated NaHCO3 (10 mL) and H2O (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a crude oil. The oil was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 22 (0.01 g, 14%) as a clear oil: 1H NMR (CDCl3): δ 1.15 (s, 3H); 1.48 (s, 3H); 1.52-1.72 (m, 3H); 1.82 (dd, 1H, 2.7, 10.2 1H); 2.03-2.20 (m, 1H); 2.22 (s, 1H); 2.24-2.48 (m, 2H); 2.54 (dd, Ja=5.1, Jb=13.5, 1H); 2.80 (dd, Ja=3.6, Jb=13.2, 1H); 3.75 (s, 3H); 5.21 (dd, Ja=7.8, Jb=12.3, 1H); 5.54 (dd, J=11.7, 1H); 6.40 (m, 1H), 6.69 (br s, 1H); 6.87 (br s, 1H); 7.12 (m, 2H); 7.28-7.45 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:39]3[CH:38]=[CH:37][C:36]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.3 g, 2.4 m mol) was coupled with 4-cyclohexyl-phenylboronic acid (615 mg, 3.0 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]phenylamino}-acetic acid methyl ester.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[C].[Pd]>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2c(-c3nc(CCC(=O)O)cs3)cnn2C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
A mixed solution of (E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (70 mg, 0.18 mmol) and 10% palladium carbon (19.43 mg, 0.18 mmol) in THF (2 mL) and methanol (2 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)propanoic acid (62.0 mg, 0.161 mmol, 88%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:18]CN=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:24]([NH:27]N)(=O)[CH3:25].C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:27][N:18]=[C:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(=O)NN
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 72 h

Procedure:
A mixture of 3.3g (0.01M) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, 2g of acetylhydrazine, 5 ml of triethylamine and 50 ml of n-butanol was heated to reflux for 3 hrs. Half of the solvent was then removed by distillation and replaced by fresh n-butanol. Refluxing was continued for 3 days. The residue obtained after evaporation was chromotographed over 100 g of silical gel(Merck 70-230 mesh) using 10% (v/v) ethanol in methylene chloride for elution. Crystallization of the pure fraction from methylene chloride/ether yielded the above maned product, m.p. 298°-300°.
Reaction SMILES: Cl.C1(C[O:9][C:10]2[CH:36]=[CH:35][C:13]3[O:14][CH:15]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[CH:34]=[CH:33][C:27]5[CH:28]=[CH:29][C:30](=[O:32])[O:31][C:26]=5[CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=2)C=CC=CC=1>O.CO.[Pd]>[OH:9][C:10]1[CH:36]=[CH:35][C:13]2[O:14][CH:15]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:34]=[CH:33][C:27]4[CH:28]=[CH:29][C:30](=[O:32])[O:31][C:26]=4[CH:25]=3)[CH2:16][O:17][C:12]=2[CH:11]=1
Reactant: O=c1ccc2ccc(OCCCNCC3COc4cc(OCc5ccccc5)ccc4O3)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1ccc2ccc(OCCCNCC3COc4cc(O)ccc4O3)cc2o1
Reaction time: 4.5 h

Procedure:
7-[3-[[(2,3-Dihydro-6-phenylmethoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.82 g, 1.6 mmole), prepared in Example 4 above, was dissolved in a mixture of 150 ml of water and 10 ml of methanol, 300 mg of 5% palladium on carbon added, and the mixture hydrogenated at 25 psi on a Parr apparatus for 4.5 hours. It was then filtered through celite and concentrated to dryness in vacuum. The residue was redissolved in methanol and boiled on a hot plate, the methanol being gradually replaced with isopropanol, and an additional 2.8 ml of 4N HCl/isopropanol was added. Upon cooling 0.37 g of the title compound, m.p. 244° C. (d), precipitated as a white solid, monohydrochloride.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=1)=[O:5])[CH3:2].[C:16](Cl)(Cl)=[O:17]>>[CH2:1]([N:3]1[C:16](=[O:17])[N:11]2[N:10]=[C:9]([C:12]([F:14])([F:15])[F:13])[S:8][C:7]2=[N:6][C:4]1=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nnc(C(F)(F)F)s1
Reactant: O=C(Cl)Cl
Product: CCn1c(=O)nc2sc(C(F)(F)F)nn2c1=O

Procedure:
, and having a melting point of about 173°-175° C., from 1.9 g. of 1-ethyl-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)urea and phosgene.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][N:2]1[C:18](OC(C)(C)C)=O.C(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:18]([N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:12]=3[C:13]=2[CH2:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C(=O)OC(C)(C)C)CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 2-tert-butyl 8-methyl 3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (0.50 g, 1.5 mmol) in DCM (5.0 mL), TFA (5.0 mL) was added. After allowing the reaction mixture to stir at room temperature for 1 h, the volatiles were evaporated, DCM and toluene (20 mL) were added and the volatiles evaporated (2×). The resulting residue was dissolved in THF/MeOH (4:1, 10 mL) and benzaldehyde (0.17 mL, 0.18 g, 1.7 mmol) and sodium triacetoxyborohydride (0.485 g, 2.3 mmol) were added. The reaction mixture was allowed to stir at room temperature overnight and 4 more equivalents of the aldehyde and reducing agent were added to cause the reaction to go to completion. The reaction mixture was then poured into saturated sodium bicarbonate solution (300 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated to give a foamy residue. Column chromatography (DCM→3% MeOH/DCM) provided methyl 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (12a in Scheme 1(h)) as a white solid (0.32 g, 66%). 1H NMR (CD3OD, 300 MHz) 8.17 (d, J=1.1 Hz, 1H), 7.73 (dd, J=8.7, 1.8 Hz, 1H), 7.44-7.27 (m, 6H), 3.88 (s, 3H), 3.83 (s, 2H), 3.73 (s, 2H), 2.95-2.88 (m, 4H) ppm; MS (ES) 321 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O.[NH2:14][NH2:15]>CCO>[NH2:11][C:10]1[NH:15][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH:9]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1Br
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2Br)n[nH]1
Yield: 69.6 %

Procedure:
To a solution of 3-(2-bromo-phenyl)-3-oxo-propionitrile (1.8 g, 8.03 mmol) in absolute EtOH (25 mL) was added hydrazine hydrate (2.3 mL, 48.2 mmol). The reaction mixture was refluxed for 23 hours, then cooled and purified directly on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 1.33 g (70% yield) of 5-amino-3-(2-bromophenyl)pyrazole as a sticky oil. 1H-NMR (d6-DMSO) δ: 11.7 (broad m, 1H, tautomers), 7.20-7.70 (broad m, 4H), 5.76 (broad m, 1H), 5.03 (broad s, 1H), 4.60 (broad s, 1H); HPLC/MS m/z: 238.0, 240.0 [MH]+.