Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH3:22].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH3:22])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1sc(-c2ccccc2)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a mixture of {3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]phenyl}methanol (2.35 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.43 g), tributylphosphine (1.43 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.62 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (2.60 g, yield 74%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 171-172° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1CN.CCC[CH2:21][N+:22](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:2]([C:3]1[N:22]([CH3:21])[C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=2)([CH3:1])([CH3:16])[CH3:17]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])ccc1CN
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)cc2cc([N+](=O)[O-])ccc21
Yield: 94 %

Procedure:
A solution of [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]methyl-amine (5.0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 mL) was heated at reflux overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over Na2SO4 and evaporated under vacuum to give 2-tert-butyl-1-methyl-5-nitro-1H-indole (5.0 g, 99%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 7.26-7.28 (m, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[CH:9]2[CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:10](=[O:19])[N:11]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: C=CCCCC(=O)N(C)CC(O)C(O)C(O)C(O)CO
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(Br)cc1)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
110 mg of 4-(4-bromophenyl)-3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)azetidin-2-one and 136 mg of N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)-hex-5-enamide are initially charged in 300 μl of triethylamine under argon in a closed tube which had been heated thoroughly beforehand. After addition of 6 mg of palladium acetate and 14 mg of triphenylphosphine, the mixture is stirred at 100° C. for 4 h. The reaction mixture is then taken up in dichloromethane, filtered and concentrated using a rotary evaporator. Purification of the residue using an SiO2 cartridge (dichloromethane/methanol 20:1–5:1) gives the product. C43H58F2N2O8Si (796)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[NH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[N:12]([S:48]([C:44]2[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=2)(=[O:50])=[O:49])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Product: CN(Cc1cc(-c2ccc(F)cc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 44 and using tert-butyl{[5-(2,4-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (113 mg), sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 mL) and pyridine-3-ylsulfonyl chloride hydrochloride (113 mg), the title compound was obtained as a pale-yellow oil (yield 110 mg, 68%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)=[C:4]([CH2:21][CH2:22][CH3:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.[Pd]>[F:20][C:16]1[N:15]=[C:14]([C:10]2[N:9]([CH2:8][C:5]3[N:6]=[N:7][CH:2]=[CH:3][C:4]=3[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCc1ccnnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-3-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-4-propyl-pyridazine (55.3 mg, 0.17 mmol), K2CO3 (30 mg) and Pd—C (10%, 6 mg) in ethanol is stirred at room temperature under H2 (H2 balloon) over night. After filtration, the solvent is removed and the residue is purified by PTLC to give the title compound. 1H NMR (CDCl3) 9.01 (d, 1H), 8.18 (dd, 1H), 7.26 (d, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.82 (dd, 1H), 6.28 (s, 2H), 2.62 (t, 2H0, 1.47–1.60 (m, 2H), 0.83 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[N+:12]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](=[O:20])[CH2:18]Br)([O-:14])=[O:13].Br>>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[N+:12]([O-:14])=[O:13])=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: Cc1[nH]c2ncccc2c1C
Agent: Br
Product: Cc1nc2n(CC(=O)c3ccccc3[N+](=O)[O-])cccc-2c1C

Procedure:
The title compound was prepared on a 5 mmol scale from 2,3-dimethylpyrrolo[2,3-b]pyridine and o-nitrophenacyl bromide in the same manner as described in example 27 yielding 1.3 g (66%) pure hydrobromide as a yellow solid. Reprocessing of the motherliquor gave additional material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[CH3:47][O:48][C:49]([O:52][CH3:53])([CH3:51])C>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:51][CH:49]([O:48][CH3:47])[O:52][CH3:53])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(CCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-])OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(10-formyldecyl) quinoline-N-oxide is dissolved in dichloromethane, and a catalytic amount of D-camphorsulfonic acid and a large excess of 2,2-dimethoxypropane are added thereto. The mixture is stirred at room temperature for 3 hours. After the reaction, the reaction solution is washed with an aqueous saturated sodium hydrogen carbonate solution, and then with water, and dried over anhydrous sodium sulfate. After removal of the solvent by distillation, the residue is purified by silica gel column procedure, whereby the captioned compound is obtained as a colorless oily substance (yield: 70.6%).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][NH:10][C:11](=[O:29])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)=[O:29])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
To a pre-cooled (0° C.) solution of 4-cyano-N′-((2R,3S)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (1.49 g, 3.45 mmol) in DMF (100 mL) was added imidazole (1.88 g, 27.63 mmol) then TBSCl (2.08 g, 13.82 mmol). The reaction was warmed slowly to room temperature, stirred for 18 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a colourless solid (1.05 g, 56%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.4 Hz, 2H), 7.92 (dm, J=8.4 Hz, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.11 (dd, J=2.3, 8.6 Hz, 1H), 6.48 (d, J=8.6 Hz, 1H), 4.43 (dq, J=4.5, 6.1 Hz, 1H), 4.35 (dd, J=4.5, 8.4 Hz, 1H), 1.37 (d, J=6.3 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[N:50]1([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH2:51][CH2:52][O:53][CH2:54][CH2:55]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(N4CCOCC4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-morpholin-4-yl-phenylamine (0.040 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.066 g of 1541I in a 76% yield: LCMS (ESI) m/z 381 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[C:18]([NH:17][CH:4]1[CH2:3][C:2]([CH3:21])([CH3:1])[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=4[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=3)=[CH:12][C:7]=2[NH:6][C:5]1=[O:16])(=[O:20])[CH3:19]
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid. (65 mg, 43%) LCMS 566 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 9.39 (s, 1H), 9.17 (s, 1H), 8.93 (t, J=5.3 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.34 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.14 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.23-4.16 (m, 1H), 4.00 (d, J=2.7 Hz, 2H), 3.10 (s, 1H), 2.09-2.04 (m, 1H), 1.88-1.84 (m, 1H), 1.84 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 19.33 g (0.1 mole) of 2-phenylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 55°-60° for 24 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed with 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 32.3 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was elut4d with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 18-20 were combined giving 3.74 g (13%) of 1-benzyl-2-phenylindole as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@H:10]([CH:33]([CH3:35])[CH3:34])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:50]=[N+:51]=[N-:52])(CCCC)CCCC)CCC>>[CH3:16][CH2:15][CH2:14][CH2:13][C:12]([N:11]([C@H:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:26]([C:31]3[N:52]=[N:51][NH:50][N:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
L-valine benzyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH3:16])[C:13]3[CH:17]=[CH:18][C:19]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:20][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH2:15]([N:14]1[C:13]2[CH:17]=[CH:18][C:19]([S:21]([C:24]([F:26])([F:25])[F:27])(=[O:22])=[O:23])=[CH:20][C:12]=2[N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=1)[CH3:16]
Reactant: CCn1c(-c2ccc(C(=O)OC)cc2)nc2cc(S(=O)(=O)C(F)(F)F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(-c2ccc(C(=O)O)cc2)nc2cc(S(=O)(=O)C(F)(F)F)ccc21
Reaction time: 3 h

Procedure:
4-(1-Ethyl-5-trifluoromethanesulfonyl-1H-benzoimidazol-2-yl)-benzoic acid methyl ester (152 mg, 0.368 mmol) was dissolved in warm ethanol (7 mL) and 1 M sodium hydroxide (1.0 mL) was added. The reaction mixture was heated to near reflux and stirred for 3 h. The reaction mixture was then partially evaporated by blowing with a stream of nitrogen and transferred to a vial containing EtOAc and 1 M aqueous hydrochloric acid. The organic phase was separated, washed with saturated brine, dried (Na2SO4) and evaporated to yield the acid 36: 1HNMR (400 MHz, d6-DMSO) δ 8.47 (d, J=1.55 Hz, 1H), 8.18 (d, J=8.66 Hz, 1H), 8.15 (d, J=8.81 Hz, 2H), 8.01 (dd, J=7.17, 1.17 Hz, 1H), 7.95 (d, J=8.25 Hz, 2H), 4.45 (q, J=7.11 Hz, 2H), 1.37 (t, J=7.09 Hz, 3H); LCMS-APCI m/z 397 [M−1]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][N:9]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(C(C)C)CC)(C)C.Cl.[N:72]1[CH:77]=[CH:76][C:75]([CH2:78][SH:79])=[CH:74][CH:73]=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:14]1([NH:13][C:11]2[O:12][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:79][CH2:78][C:75]3[CH:76]=[CH:77][N:72]=[CH:73][CH:74]=3)=[N:9][N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: SCc1ccncc1
Reactant: Brc1ccccc1-c1nnc(Nc2ccccc2)o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(Nc2nnc(-c3ccccc3SCc3ccncc3)o2)cc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A vessel containing 5-(2-bromophenyl)-N-phenyl-1,3,4-oxadiazol-2-amine (220 mg, 0.70 mmol; Reference Compound 7-(1)), tris(dibenzylideneacetone)dipalladium (33 mg, 0.035 mmol) and Xantphos (81 mg, 0.14 mmol) was replaced with nitrogen gas. To the vessel were added dioxane (5.0 mL), diisopropylethylamine (0.43 mL, 2.5 mmol) and 4-pyridinemethanethiol hydrochloride (210 mg, 1.3 mmol) successively at room temperature, and then the mixture was refluxed overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (15 mL). The ethyl acetate solution was washed with a saturated brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated under a reduced pressure. To the residue was added ethanol and a precipitated solid was filtered off and dried to give 180 mg (70%) of the titled compound as a pale brown solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][OH:15]>O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:12][CH2:13][CH2:14][OH:15])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccnc(SCCCO)n1
Yield: 117 %

Procedure:
A mixture of 2-thiocytosine (0.88 g.), sodium hydroxide (0.32 g.), water (5 ml.) and 3-chloropropanol (0.8 g.) was heated at 90° for 1 hour and then cooled. The mixture was extracted with EtOAc and the extract dried and then evaporated to dryness to give 4-amino-2-(3-hydroxypropylthio)pyrimidine (1.5 g.) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([Br:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:14][CH3:15].[N+:16]([O-])([OH:18])=[O:17].ClCCl.O>ClCCl>[OH:1][C:2]1[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:5]([C:8](=[O:13])[C:9]([Br:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C(=O)C(C)(C)Br)ccc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)C(C)(C)Br)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 4'-hydroxy-3'-methoxy-2-bromoisobutyrophenone (10.0 g) in dichloromethane (80 ml) was gradually added 2M HNO3 -dichloromethane (19 ml). The mixture was stirred for 2 hours at 10° C. after which water (100 ml) was added. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. Ether (20 ml) was added. The resulting crystals were filtered and washed with ether. Yield 3.3 g.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:39].C(OCC)(=O)C>>[ClH:39].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ncccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ncccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To 0.69 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 25 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 42 hours. The solvent was distilled off under reduced pressure, a mixed solution of ethyl acetate and ethanol (5:1) was added to the resultant residue, and the solid was filtered off to obtain 0.59 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1N=CN=[C:4]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[S:13](=[O:27])(=[O:26])[C:14]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])=[O:10])[CH:3]=1.Cl[C:30]1N=CN=[C:32](NC(C2NS(=O)(=O)C3C4C(=CC=CC=4)C=CC=3C=2O)=O)[CH:31]=1.CI>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[S:13](=[O:26])(=[O:27])[C:14]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])=[O:10])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CN1C(C(=O)Nc2cc(Cl)ncn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Solvent: CI
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
N-(6-Chloro-4-pyrimidyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 263° C (decomp.), from N-(6-chloro-4-pyrimidyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide and methyl iodide.