Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:4][C:3]=1[CH:15]=[O:16].[OH:17][CH2:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]1[CH2:20][CH2:19][CH2:18][O:17][CH:15]1[C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: OCCCO
Reactant: Cc1ccccc1-c1ccc(O)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(O)c(C2OCCCO2)c1
Yield: 89 %

Procedure:
A solution of 4-hydroxy-2′-methyl-biphenyl-3-carbaldehyde (18.8 mmol) in toluene (100 mL) was added 1,3-dihydroxypropane (65.7 mmol) and p-toluenesulfonic acid (cat) and heated at reflux overnight in a Dean-Stark set-up. The reaction was cooled and washed with a solution of Na2CO3 (aq, 1 M). Evaporation in vacuo gave the title product as brown oil in 89% yield. 1H-NMR (CDCl3) δ 9.61 (bs, 1H), 7.34-7.10 (m, 6H), 6.87 (d, 1H), 5.77 (s,1H), 4.13-4.07 (m, 2H), 3.95-3.86 (m, 2H), 2.20 (s, 3H), 2.18-1.96 (m, 1H), 1.40 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)CCCN=C=NCC.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.CN.C1COCC1>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:31][CH3:30])=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a stirring solution of 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoic acid (100 mg, 0.259 mmol) in dichloromethane (10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (74 mg, 0.388 mmol), triethylamine (0.1 mL, 0.77 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (79 mg, 0.518 mmol) and stirred for 10 min. To this methyl amine solution in THF (0.518 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-80% ethyl acetate in pet ether) afforded the title compound as a solid (50 mg, 50%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.OC1C=CC(C=O)=CC=1>>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting 4-Hydroxy-benzaldehyde provided the title compound. MS: (M+H m/z=264.2).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc2c(cn1)[nH]c1ncc(Cl)cc12
Temperature: 60 °C
Yield: 64.9 %

Procedure:
A solution of 3-chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (24.2 mg, 67.4 μmol) in THF (1.3 mL) was treated with TBAF (398 μL, 1.35 mmol) and heated to 60° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The resultant residue was dissolved in DCM/EtOAc, absorbed onto silica gel, and purified by flash chromatography (silica, 4 g column, Biotage, 1-20% methanol in DCM containing 0 1% 7N ammonia in MeOH). Collecting appropriate fractions afforded a solid which was further purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (10 mg, 66%). 1H NMR (400 MHz, DMSO-D6): 13.07 (s, 1H), 9.05 (d, J=0.9 Hz, 1H), 8.95 (d, J 2.4 Hz, 1H), 8.92 (d, J=0.9 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H). LCMS (Method E): RT=3.98 min, M+H+=229.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH2:5][CH2:4][C:3]1=O.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[BH4-].[Na+].[ClH:22]>>[ClH:12].[ClH:22].[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH2:5][CH2:4][CH:3]1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: CC1C(=O)CCc2cccc(Cl)c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC1c2c(Cl)cccc2CCC1N1CCNCC1

Procedure:
Using the method of Example 11, 1.94 g (10 mmol) of 1-methyl-8-chloro-2-tetralone were treated with piperazine followed by reduction with sodium borohydride and treatment with HCl to produce 0.67 g of the title compound as colorless crystals; m.p. >200° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:16][C:15]=2[N:14]([CH3:39])[C:13]1=[O:40])(C(C)(C)C)(C)C.Cl>C(O)C>[ClH:29].[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:40])[N:14]([CH3:39])[C:15]=3[N:16]=[C:17]2[O:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:28][CH:27]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OCCN1CCOCC1)n2Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OCCN1CCOCC1)n2Cc1ccc(Cl)cc1
Yield: 57 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione (0.27 g, 0.46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) and stirred at room temperature for 1 h. The reaction was evaporated and azeotroped with methanol (3×10 mL). The solid residue was triturated with methanol (5 mL) and filtered. The white solid was washed with diethyl ether (2×10 mL) and high vacuum dried to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride (0.14, 57% yield) as a white solid. LCMS retention time=1.908 min and 95% purity, LCMS MH+ 478. 1H NMR (DMSO-d6) δ 11.54 (s, HCl), 7.38 (dd, 4H, J=12 and 28 Hz), 5.33 (2, 2H), 4.82-4.89 (m, 2H), 3.75-3.95 (m, 2H), 3.58-3.64 (m, 2H), 3.33-3.44 (m, 5H), 3.06 (m, 2H), 1.62-1.72 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:45])[CH2:11][N:12]([CH2:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[C:20]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:26])=[CH:19][N:18]([CH3:36])[C:17]=2[C:16]=1[CH2:37][O:38]CC[Si](C)(C)C)[CH3:13].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:45])[CH2:11][N:12]([CH2:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[C:20]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:26])=[CH:19][N:18]([CH3:36])[C:17]=2[C:16]=1[CH2:37][OH:38])[CH3:13]
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1cc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1cc2ccccc2o1
Yield: 78.7 %

Procedure:
A solution of 154 mg of 2-{[[2-(1-benzofuran-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 4% MeOH in CH2Cl2 provides 103 mg of the title compound as a pale yellow solid. Recrystallization from acetonitrile affords white needles.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH:8]=[O:9]>C1COCC1>[F:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:1])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]
Reactant: C[Mg+]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethereal solution (17.41 ml, 52.24 mmol, 3M) of MeMgBr was slowly added at −78° C. to a solution of 3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 ml). The reaction mixture was stirred at room temperature for 16 h and was cooled (0° C.) and was quenched, sequentially, with excess ethyl acetate (10 ml) and water (5 ml). Excess anhydrous MgSO4 (5 g) was added and stirred for 30 minutes at room temperature. The suspension was filtered over celite and the solids were washed with ethyl acetate (2×25 ml). The combined filtrate was evaporated to obtain the product in quantitative yield (7.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11](C3C4CNC(=O)C=4C=CN=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C2CNC(=O)C=2C=CN=1.Br[C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH2:46][NH:47][C:48]2=[O:53]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:44]3[CH:52]=[CH:51][CH:50]=[C:49]4[C:45]=3[CH2:46][NH:47][C:48]4=[O:53])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NCc2c(Br)cccc21
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C1NCc2c1ccnc2Cl
Product: O=C1NCc2c1cccc2-c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The synthesis of the title compound is performed starting from 100 mg (0.25 mmol) of the product from step 3 of example 1 in a manner analogous to the synthesis of the compound from example 1. In step 4, instead of the compound from example 22A, 4-bromo-2,3-dihydroisoindol-1-on (63 mg, 0.30 mmol) is used. The result is 74 mg (65% of theoretical yield) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)(C)C.[ClH:27].CO>>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[ClH:27]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(-c2cccc(N)c2)cc1

Procedure:
A solution of [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (5 g, 13 mmol) in HCl/MeOH (4M, 150 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was washed with ether to give the target compound N-((3′-aminobiphenyl-4-yl)methyl)methanesulfonamide as its HCl salt (3.0 g, 71%). 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.71 (m, 6H), 7.46 (d, J=7.8 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 4.19 (s, 2H), 2.87 (s, 3H). MS (ESI) m/e (M+H+): 277.0.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:12]([NH:16][NH:17][P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([N:16]([C:1](=[O:3])[CH3:2])[NH:17][P:18]([O:20][CH3:21])([O:22][CH3:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: COP(=O)(NNC(C)(C)C)OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COP(=O)(NN(C(C)=O)C(C)(C)C)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Acetylchloride (10.8 g) was added dropwise to a stirred solution of triethylamine (13.9 g) and 1-t-butyl-2-dimethoxyphosphoryl hydrazine (9.0 g) in methylenechloride (120 ml) maintained at -20° C. After the addition was complete, the temperature was allowed to rise to 0° C. and kept at this temperature for 1 hour. The mixture was then allowed to warm up to ambient temperature during 2 hours, and the content of the reaction vessel was then stripped to dryness on the rotary evaporator. The residue was extracted with diethylether and the organic extracts dried over magnesium sulfate, filtered and evaporated to dryness, leaving an oil which was subjected to high vacuum for several hours yielding 10.4 g of product.
Reaction SMILES: [Cr](O)(O)(=O)=O.[CH3:6][C:7]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])([CH3:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH2:23]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:14][C:7]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]([OH:23])=[O:19])([CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(C)(C)c1cccc(C=O)c1
Reactant: O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCCCC(C)(C)c1cccc(C(=O)O)c1
Reaction time: 0.03 h
Yield: 99 %

Procedure:
Chromic acid (105.4 mg, 1.05 mmol, 1.2 eq) was dissolved in acetic acid (2 ml), and a solution of 3-(1,1-dimethylheptyl)benzaldehyde (205 mg, 0.878 mmol) in acetic acid (2 ml) was added to the solution under ice-cooling, which was followed by stirring for 2 minutes. The mixture was further stirred at room temperature for 30 minutes. Conc. sulfuric acid (2 drops) was added, and the mixture was stirred for 3 hours. To this reaction mixture, water (10 ml) was added, and the mixture was extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=2/1) to give 3-(1,1-dimethylheptyl)benzoic acid (205 mg, 99.0%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:23][CH2:24][C:25](O)=[O:26].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:24](=[O:23])[CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CO
Reactant: Cc1cnc(-c2nc(N3CCC(N)CC3)ccc2Cl)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(-c2nc(N3CCC(NC(=O)CO)CC3)ccc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.2 %

Procedure:
To a mixture of 1-(3-chloro-3′,5′-dimethyl-2,2′-bipyridin-6-yl)piperidin-4-amine (hydrochloride salt) (60 mg, 0.13 mmol) and 2-hydroxyacetic acid (14.8 mg, 0.20 mmol) in DMF (1.3 mL) were added (in this order) NMM (105 mg, 1.0 mmol), HOBT (26.3 mg, 0.20 mmol), and EDCI (38.5 mg, 0.20 mmol). The resulting solution was stirred at rt for 3.5 h. Water was added, and the mixture was stirred at rt overnight. Filtered off the solid that had crashed out, washed with water, and dried to get 23 mg (47%) of the title compound as a white solid. m/z (APCI+) for C19H23N4O2Cl 375.10 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1 H) 7.67 (d, J=9.09 Hz, 1 H) 7.62 (d, J=8.34 Hz, 1H) 7.53 (s, 1 H) 6.93 (d, J=9.35 Hz, 1 H) 5.37 (t, J=5.94 Hz, 1 H) 4.18 (d, J=13.64 Hz, 2H) 3.82-3.94 (m, 1 H) 3.78 (d, J=5.81 Hz, 2 H) 2.91 (t, J=11.49 Hz, 2 H) 2.32 (s, 3 H) 2.08 (s, 3 H) 1.72 (dd, J=12.76, 2.91 Hz, 2 H) 1.41-1.54 (m, 2 H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>C(=S)=S>[Cl:17][C:18]1[C:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)=[CH:23][CH:24]=[CH:25][N:26]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: O=C(c1ccc(-c2ccccc2)cc1)c1cccnc1Cl

Procedure:
26.7 g AlCl3 is added slowly while stirring to a solution of 9.2 g biphenyl and 10.6 g 2-chloronicotinoyl chloride in 170 ml carbon disulfide. The mixture is refluxed 5 hrs. After cooling, the S2C layer is poured off, and the residue is added to acidic ice:water, basified and extracted with methylene chloride. The combined extracts are washed, dried (MgSO4) and solvent removed in vacuo. The crude product is chromatographed on a silicagel column and eluted with benzene:ethyl acetate 15:1 Yield: 5 g of title product, m.p. 128°-32° C.; UV (ethanol): λmax. 295 nm, ε: 27,260; Cl 11.96 (12.07).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66].C(O)(=O)C>CO>[C:65]([CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:67])=[O:66]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.052 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 204 μl einer of a 15% aqueous solution of 4-oxobutanoic acid were combined in 2 ml of methanol and admixed with 23.4 mg (0.252 mmol) of borane-pyridine complex and 6 μl of acetic acid. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 38 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([C:19]1[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([NH2:27])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>CN(C=O)C>[C:15]([C:19]1[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3[se]c4c(c23)CCCC4)c(C(N)=O)s1

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (700 mg, 2.57 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 5-tert-butyl-3-aminothiophene-2-carboxamide (700 mg, 3.6 mmol) and powdered NaOH (310 mg, 7.7 mmol) at rt. Work-up of the mixture as described in example 2, gave the product as a yellow color solid, mp 240-244° C. 1H NMR (400 MHz, DMSO-d6): δ 11.38 (1H, s, exchangeable with D2O), 8.45 (1H, s), 8.27 (1H, s), 7.53 (2H, s, exchangeable with D2O), 3.15 (2H, br s), 2.90 (2H, br s), 1.84-1.85 (4H, m), 1.39 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 166.1, 158.0, 153.1, 151.4, 143.4, 138.2, 128.2, 119.5, 119.2, 109.2, 34.5, 31.7, 27.7, 27.4, 22.4, 22.1; LC-MS (positive ion mode): m/z 433, 435 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][N:30]3COCC[Si](C)(C)C)=[CH:26][CH:25]=2)=[CH:20]1.C(OCC)(=O)C>O1CCCC1>[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:20]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccsc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccsc3)ccc12
Temperature: 66 °C

Procedure:
8.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 570 mg of N-[6-(3-thiophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours. The heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with cyclohexane/ethyl acetate (60/40 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×5 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 40° C.) to give, after drying (90 Pa; 50° C.), 260 mg of N-[6-(3-thiophenyl)-1H-indazol-3-yl] butanamide in the form of a white solid melting at about 198° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[CH:4]([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].C=CC>[Pd].C1(C)C=CC=CC=1>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8]
Reactant: CC1=CCCC(C)C1=O
Reactant: COCCN
Agent: [Pd]
Solvent: C=CC
Solvent: Cc1ccccc1
Product: COCCNc1c(C)cccc1C
Yield: 34.6 %

Procedure:
2.0 g (0.0161 mole) of 2,6-dimethyl-cyclohex-2-en-1-one, 50 ml of toluene, 1.8 g (0.024 mole) of 2-methoxyethylamine and 0.5 g of palladium on charcoal (5%) are heated with a starting pressure of 17 bars (7 bars propylene and 10 bars nitrogen) for 10 hours at 180° C. After cooling, the catalyst is filtered off and the filter residue is washed with ether and toluene. The solvent is evaporated off to leave 1.0 g of crude N-(2-methoxyethyl)-2,6-dimethylaniline, from which is obtained, by distillation in high vacuum, 0.4 g (13% of theory) of pure N-(2-methoxyethyl)-2,6-dimethylaniline; b.p. 61°-62° C./ 0.1 Torr.