Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[BH-](O[C:51]([CH3:53])=[O:52])(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:52][C:51]1[CH:53]=[CH:5][C:7]([CH2:8][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:40][CH:39]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde10,411,879 (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. Na(OAc)3BH (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34. Found, 650.2.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.O>C(Cl)Cl>[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OCC(COc2ccc(OCc3ccccc3)cc2)O1
Solvent: ClCCl
Solvent: O
Product: OCC(O)COc1ccc(OCc2ccccc2)cc1
Yield: 38.3 %

Procedure:
A mixture of 8.98 g of 2,2-dimethyl-4-[[4-(phenylmethoxy)phenoxy]methyl]-1,3-dioxolane, 15 g of a strongly acidic ion exchange resin and 200 ml of water was refluxed for 24 hours, then allowed to cool and methylene chloride was added. The mixture was filtered and the organic layer separated and saved. The aqueous layer was extracted several times with methylene chloride. All organic solutions were combined, dried and evaporated, giving 3.0 g of the desired compound, mp 125°-127° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][N:23]([CH3:36])[C:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31]C)=[O:30])=[O:25])=[CH:4][CH:3]=1.O[Li].O.Cl>CO.O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][N:23]([CH3:36])[C:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([OH:31])=[O:30])=[O:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CN1CCN(Cc2cccc(-c3cc(CN(C)C(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 80 °C
Yield: 113.6 %

Procedure:
To a solution of methyl 3-{[({6-fluoro-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)(methyl)amino]carbonyl}benzoate (0.20 g, 0.409 mmol) in MeOH/H2O (1.2/0.6 mL) was added LiOH.H2O (0.086 g, 2.05 mmol). The mixture was heated in a microwave at 80° C. for 30 min following which it was acidified with HCl, concentrated and the concentrate purified using a Gilson HPLC to afford the title compound 0.221 g (quantitative). LC-MS m/z 476 (M+H)+.
Reaction SMILES: [C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH2:9][CH:10]2[CH2:37][CH2:36][C:13]3[N:14](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:15]=[N:16][C:12]=3[CH2:11]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=CC=1>C(O)(=O)C.O>[C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][CH2:9][CH:10]2[CH2:37][CH2:36][C:13]3[NH:14][CH:15]=[N:16][C:12]=3[CH2:11]2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(COCC3CCc4c(ncn4C(c4ccccc4)(c4ccccc4)c4ccccc4)C3)cc2)cc1
Agent: c1ccc(-c2ccc(COCC3CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4C3)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2ccc(COCC3CCc4[nH]cnc4C3)cc2)cc1
Temperature: 90 °C

Procedure:
A solution of a mixture of 5-((biphenyl-4-yl)methoxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((biphenyl-4-yl)methoxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (440 mg, 0.78 mmol) in a mixture of acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2.25 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 220 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:36]#[N:37]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:36]#[N:37])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 120 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.5 g, 0.84 mmol) and copper(I) cyanide (0.151 g, 1.7 mmol) were suspended in anhydrous N,N-dimethylformamide (4 mL). The mixture was stirred at 120° C., under nitrogen for 24 h. Upon cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous ammonium chloride solution (3×15 mL). The organic phase was passed through a short plug of Celite followed by a short plug of silica gel (Merck silica gel 60, 40-63 μm), eluting with ethyl acetate. The filtrate was concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, (1R,2S,7R,8S)-3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.398 g, 0.808 mmol, 96%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.15 (1H, m), 1.34-1.61 (5H, m), 2.48-2.48 (1H, m), 2.60 (1H, d, J=3.3 Hz), 2.90 (1H, d, J=9.4 Hz), 3.48 (1H, d, J=9.4 Hz), 4.38 (1H, d, J=15.6 Hz), 4.96 (1H, d, J=15.4 Hz), 7.11-7.16 (2H, m), 7.31 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.60 (1H, d, J=8.6 Hz), 8.02 (1H, dd, J1=8.6 Hz, J2=2.5 Hz), 8.37 (1H, s). LC-MS (ESI) calculated for C25H21FN4O4S 492.13. found 493.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.Cl[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4cccnc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (710 mg, 1.19 mmol), 3-(chloromethyl)pyridine hydrochloride (794 mg, 4.84 mmol), potassium carbonate (1.337 g, 9.67 mmol) in acetone (21 mL) and water (7 mL). Stir and heat at reflux for 24 h. Allow reaction mixture to cool to room temperature, and remove the acetone under vacuum. Add ethyl acetate to the reaction mixture and separate the organic layer. Extract the organic layer with saturated aqueous NaCl solution, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Chromatograph the residue on silica gel eluting with 30% methanol/ethyl acetate to give the title compound: Rf=0.16 (silica gel, 20% methanol/ethyl acetate)]. Elemental Analysis calculated for C41H44N5O5: C 71.59; H 6.59; N 10.18; Found: C 69.84; H 6.75; N 9.82.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[I:12].[H-].[Na+].[C:15](Cl)([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.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:6]=[C:5]2[I:12]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cc2[nH]nc(I)c2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1Br)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of 3.0 g of 5-bromo-6-fluoro-3-iodo-1H-indazole in N,N-dimethylformamide in 150 mL was added 0.42 g of sodium hydride at room temperature, and the resultant solution was stirred for 15 minutes, added with 2.45 g of trityl-chloride, and stirred at this temperature for 1 hour. After adding water and diluting with ethyl acetate, washing successively with aqueous ammonium chloride and saturated brine and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30-1:5), and the resultant product was added with n-hexane. Then the precipitated crystals were washed with diethyl ether:n-hexane=1:10, to afford 3.79 g of the title compound as colorless crystals.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].Cl>C(Cl)Cl>[ClH:1].[NH2:2][C@@H:3]([CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: C[C@H](N)CCCCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](N)CCCCC(=O)O
Yield: 89.5 %

Procedure:
89 g (374 mmol) of tert.butyl (S)-6-aminoheptanoate hydrochloride are dissolved in 1.3 l of methylene chloride. The solution is saturated with hydrogen chloride and heated to reflux for 4 hours. After filtering off and drying the precipitate formed there are obtained 60.8 g (89.5%) of (S)-6-aminoheptanoic acid hydrochloride, m.p. 157°-160°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19](Cl)=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:19]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:20]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise at 0° C. under nitrogen to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].[CH3:62][O:63][CH:64]([O:72][CH3:73])[CH2:65][NH:66][CH2:67][C:68]([F:71])([F:70])[F:69].C(N(CC)CC)C>CN(C=O)C>[CH3:73][O:72][CH:64]([O:63][CH3:62])[CH2:65][N:66]([CH2:67][C:68]([F:69])([F:70])[F:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]1[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]2[CH2:42][CH2:43][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:60][CH2:61]2)[C:26]=1[F:25]
Reactant: COC(CNCC(F)(F)F)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(CN(CC(F)(F)F)C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)OC
Temperature: 20 °C
Reaction time: 72 h

Procedure:
HATU (0.30 g) was added in one portion to a cooled solution (ice bath) of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.32 g) and N-(2,2-dimethoxyethyl)-2,2,2-trifluoroethanamine [Amine 14] (0.17 g) and triethylamine (0.25 mL) in DMF (7 mL). The mixture was stirred at 20° C. for 3 days, then partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 5% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.15 g.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>O1CCOCC1>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL) was cooled to 10° C. Bromine (1.1 equiv, 61.6 mmol) was added dropwise to the reaction mixture. After 10 min, the cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo, poured into water (100 mL), and extracted with (3×100 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to a tan solid (18.2 g) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][S:17]SC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:8]([S:17][CH3:16])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CSSC
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O

Procedure:
In analogy to the procedure described for the synthesis of example B.1, the title compound was prepared from 2-methoxy-4-(trifluoromethyl)benzoic acid (commercial) and dimethyldisulfide.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>C(#N)C>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: COCCN
Solvent: CC#N
Product: COCCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-methoxyethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 254 (38), 131 (8), 88 (bp), 58 (8), 56 (12).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)#[N:26]>O1CCCC1>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (6 ml) was added 4-cyanophenyl isocyanate (176 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 160 mg (50.6%) of the desired product as a solid.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Cl:8][C:9]1[CH:17]=[C:16]2[C:12](/[C:13](=[CH:19]/[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])/[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.C(O)(=O)C>CO>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]([CH:19]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a solution of nitromethane (Aldrich) (1.7 g, 27 mmol) in methanol (20 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (5.9 g, 27 mmol). After the mixture was stirred at room temperature for 10 min, a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (3.4 g, 14 mmol) in methanol (20 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then acetic acid (2.5 g, 41 mmol) was added. The mixture was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3) to give the racemic 6-chloro-3-(3,3-dimethyl-1-nitromethyl-butyl)-1,3-dihydro-indol-2-one as a white foam (3.8 g, 90%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[C@H:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:16][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14]1.C(N(CC)CC)C.[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.O>C(#N)C>[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:12][C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14]2)=[O:46])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution of the compound (1.1 g) obtained in step 6 and triethylamine (664 μL) in acetonitrile (10 mL) was added 4-chlorobenzoyl chloride (308 μL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→40% ethyl acetate/hexane) to give the title compound (0.80 g, 78%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([OH:35])[C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C1C[O:39][CH2:38][CH2:37]1.N1C=CC=CC=1.C(Cl)(=O)C>O>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:31])([CH3:32])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[O:35][C:38](=[O:39])[CH3:37])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21
Reactant: C1CCOC1
Solvent: O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.2 g (4.6 mmol) of benzyl 2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate, 50 ml of THF and 380 μl (4.6 mmol) of pyridine are introduced into a flask. 330 μl (4.6 mmol) of acetyl chloride are added dropwise and the reaction mixture is stirred at room temperature for 8 hours. It is poured into water and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of hexane and dichloromethane (90:10). After evaporation of the solvents, 1.8 g (77%) of the expected product are collected in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.