Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:5]=1[CH:6]=O.Cl.[CH3:22][C:23]([CH3:25])=[O:24]>O>[CH3:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:5]=1[CH:6]=[CH:22][C:23](=[O:24])[CH3:25]
Reactant: CC(C)=O
Reactant: Cc1cc(OCc2ccccc2C)ccc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(OCc2ccccc2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2N NaOH(aq) (0.6 mL) was added to a solution of 31.3 (100 mg, 0.42 mmol) in acetone (1 mL). The reaction was stirred at room temperature overnight and then taken up in water. The aqueous solution was acidified with 1N HCl(aq) (1.5 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The resultant residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 74 mg (63%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-one (31.4). LC/MSD m/e: 281.4 (M+H); 1H NMR (400 MHz) (acetone-d6) δ 7.83 (1H, d, J=16), 7.70 (1H, m), 7.46 (1H, m), 7.25 (3H, m), 6.96 (2H, m), 6.63 (1H, d, J=16 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:15][CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-(trifluoromethyl)phenol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[NH:26]1[C:22]([C:18]2[CH:17]=[C:16]([NH:15][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH:21]=[CH:20][CH:19]=2)=[N:23][N:24]=[N:25]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc2ccccc2c1
Yield: 56.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 2-naphthalenesulfonyl chloride (13 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 10 mg (57%) of the title compound. MS (ESI+) calcd for C17H13N5O2S 351.078995, found 351.080505
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:30]([C:31]([NH2:33])=[O:32])[C:29]=1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:31]([C:30]1[C:29]([OH:37])=[C:28]([CH:36]=[CH:35][CH:34]=1)[O:27][CH2:26][CH2:25][N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)(=[O:32])[NH2:33]
Reactant: NC(=O)c1cccc(OCCNCc2ccccc2)c1O
Reactant: COCCOc1ccc(OCC2CO2)cc1
Product: COCCOc1ccc(OCC(O)CN(CCOc2cccc(C(N)=O)c2O)Cc2ccccc2)cc1

Procedure:
By reacting 2.5 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene with 2.9 g of crude 3-(2-benzylaminoethoxy)salicylamide obtained according to Example (25c), analogously to Example (4a), 1-[N-[2-(3-carbamoyl-2-hydroxyphenoxy)ethyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is obtained as an oil which is further processed in this state
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][OH:3].[CH3:5][C:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:20]=[C:21]([C:25]4([C:31](OCC)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[N:7]=1>C(O)C>[OH:3][CH2:2][CH2:1][NH:4][C:31]([C:25]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18][C:15]3[CH:16]=[CH:17][C:12]([N:8]4[C:9](=[O:11])[NH:10][C:6]([CH3:5])=[N:7]4)=[CH:13][CH:14]=3)[CH:20]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:32]
Reactant: CCOC(=O)C1(c2cccc(Sc3ccc(-n4nc(C)[nH]c4=O)cc3)c2)CCOCC1
Reactant: NCCO
Solvent: CCO
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)NCCO)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
2-Ethanolamine (6.0 mmol) is added to a solution of ethyl 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxylate (1.0 mmol) (example 19) in ethanol and the mixture are refluxed. All the volatiles are removed under reduced pressure and the residue is purified by column chromatography over silica gel to afford the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([N:15]2[CH2:20][C@@H:19]3[CH2:21][C@H:16]2[CH2:17][N:18]3C(OC(C)(C)C)=O)[CH:12]=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[ClH:29].[C:1]([C:9]1[CH:10]=[C:11]([N:15]2[CH2:20][C@@H:19]3[CH2:21][C@H:16]2[CH2:17][NH:18]3)[CH:12]=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cncc(N2C[C@@H]3C[C@H]2CN3)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
(1S,4S)-5-(5-Benzoyl-3-pyridyl)-2-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.360 g, 0.95 mmol) was dissolved in ethyl acetate (30 mL). The solution was saturated with HCl gas at 5° C. (ice water bath) and was allowed to stand overnight at room temperature. After evaporation of the solvent under vacuum, the residue was triturated with ether. The formed precipitate was dried under vacuum to give 0.30 g (90%) of a yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 160 °C
Reaction time: 6 h
Yield: 3.9 %

Procedure:
N-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (198 mg, 0.513 mmol) and methyl 2-fluorobenzoate (0.0653 mL, 0.513 mmol) were dissolved in dimethylsulfoxide (5 mL). To this solution, potassium carbonate (142 mg, 1.03 mmol) was added and the mixture was stirred for 6 hours at 160° C. Subsequently, the mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.80 mg (4%) of the desired compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26](B(O)O)[CH:27]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH2:12][CH2:11][C@:10]4([CH2:16][CH2:15][N:14]([CH3:17])[C:13]4=[O:18])[N:9]=3)[CH:3]=2)[CH:27]=1)[CH3:20]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CN1CC[C@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2ccnc(C3=N[C@]4(CC3)CCN(C)C4=O)c2)c1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a solution of (5R)-2-(4-bromo-pyridin-2-yl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (0.1670 g, 0.5419 mmol) in MeCN (2 mL) and water (0.3000 mL) in a Smith microwave vessel was added (5-ethoxy-2-fluoro-phenyl)boronic acid (0.1097 g, 0.5961 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.0114 g, 0.0163 mmol) and sodium carbonate (0.1149 g, 1.0838 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 40 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvents gave an amber oil, which was further purified by silica gel chromatography to give the desired product (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (0.2000 g, 0.5443 mmol) (D55) as an amber oil;
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-fluorobenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a pale yellow needle-like crystals (yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl.Cl[CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1OCCCN1CCOCC1
Yield: 73.7 %

Procedure:
A solution of N-{3-fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide (25.6 g, 54 mmol), N-(3-chloropropyl)morpholine hydrochloride (11.7 g, 592 mmol) and potassium carbonate (16.6 g, 120 mmol) in DMF (300 mL) was heated to 80° C. overnight. Upon cooling, a majority of the DMF (250 mL) was removed on a rotary evaporator, 5% aqueous LiCl (300 mL) was added and the mixture was sonicated at room temperature. The solid was filtered, suspended in 1N HCl and washed with ethyl acetate (2×300 mL). The solution was adjusted to pH 14 using 2N sodium hydroxide and subsequently extracted with dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide as a yellow solid (24 g, 74%). 1H NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 8.46 (d, 1H), 7.81 (dd, 1H), 7.57 (t, 1H), 7.53 (s, 1H), 7.42 (s, 2H), 7.34-7.20 (m, 6H), 6.39 (d, 1H), 4.27 (t, 2H), 4.03 (s, 3H), 3.71 (m, 4H), 3.65 (q, 2H), 2.91 (t, 2H), 2.56 (br s, 4H), 2.13 (m, 2H); 13C NMR (100 MHz, d6-DMSO): δ 160.1, 160.0, 159.5, 155.2, 152.7, 152.6, 150.2, 149.5, 147.1, 139.7, 137.3, 137.1, 129.3, 129.1, 126.9, 124.8, 117.9, 115.1, 109.2, 102.7, 99.6, 67.4, 66.9, 56.5, 55.5, 54.1, 41.3, 35.2, 26.4; IR (cm−1): 1655, 1506, 1483, 1431, 1350, 1302, 1248, 1221, 1176, 1119, 864, 843, 804, 741, 700; LC/MS (M+H=603).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:18][C:19]1([CH3:27])[O:26][C:24](=[O:25])[CH2:23][C:21](=[O:22])[O:20]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH:23]2[C:24](=[O:25])[O:26][C:19]([CH3:27])([CH3:18])[O:20][C:21]2=[O:22])=[CH:12][CH:11]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.165 g, 1.42 mmol) was added to a solution of 4-chlorobenzaldehyde (1.00 g, 7.11 mmol) and Meldrum's acid (1.03 g, 7.11 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.80 g, 7.11 mmol) was added. Stirring was continued for 3 hours and EtOH removed under reduced pressure. The residue was diluted with i-PrOH and filtered to provide the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH2:26]([NH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:27]>>[CH2:26]([NH:28][CH2:29][CH:30]1[CH2:31][N:32]([C:16]2[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=2[F:21])[CH2:33][CH2:34][O:35]1)[CH3:27]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCCO1
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(ethylaminomethyl)morpholine, the reaction is similarly carried out as Example 26 to give 7-[2-(ethylaminomethyl)morpholino]-1(2,4-difluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 226°-229° C. with decomposition. Examle 28
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([O:32]CC1C=CC=CC=1)=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:6]>[Pd]>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:13][CH:14]=1)=[O:6]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
L-valine benzyl ester hydrochloride 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: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1
Reactant: CCCCCCC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: N
Product: CCCCCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C

Procedure:
A mixture of 1.98 parts of 7-chloro-2-(2-enanthylhydrazino)-5-phenyl-3H-1,4-benzodiazepine and 30 parts of polyphosphoric acid is heated at 170° C to 180° C for 2 hours. To the mixture is added 200 parts by volume of ice-water and the resulting solution is neutralized with concentrated aqueous ammonia under ice-cooling, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. The residue is recrystallized from aqueous acetone to yield 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless plates melting at 75° C to 78° C (sintering).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[S:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:21][C:20]2[CH:22]=[CH:23][C:17]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CCCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-propoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 84%)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:12][C:11](=[O:13])[CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[O:23])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[O:23]=[C:9]1[CH:8]([CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:12][C:11]([O:13][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:10]1[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of 4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (100 mg, 0.25 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added the pivaloyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 3-oxo-4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (102 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][CH3:18])[CH2:9][O:10]2)=O.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CCCCCC>[OH:2][CH2:3][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([N:15]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:9][O:10]2
Reactant: CCCN(C(C)C)C1COc2cccc(C(=O)OC)c2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCN(C(C)C)C1COc2cccc(CO)c2C1
Temperature: -78 °C
Yield: 96.5 %

Procedure:
5-Methyloxycarbonyl-3-(N-isopropyl-N-propylamino)chroman (0.69 g, 2.36 mmol) was dissolved in 25 mL of dry methylene chloride and cooled to -78° C. A 1M solution of diisobutylaluminum hydride in hexane (6.6 mL) was added dropwise and the reaction was allowed to warm to room temperature for 50 min. A 1M solution of KOH was added dropwise and then the reaction was put into the refrigerator over night. The solution was poured through a pad of Na2SO4, dried (Na2SO4), filtered and the solvent removed in vacuo to give 0.60 g (97% yield) of the title compound as a clear oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44](CN([C@@H](C(C)C)C(OC)=O)[C:47]3=O)=CC=2)=[CH:37]C=1.CC1(C)CCC(C)(C)C2C=C(C(Cl)=O)C=CC1=2>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1]([C:2]4[CH:3]=[CH:4][C:5]5[C:48]([CH3:44])([CH3:47])[CH2:49][CH2:41][C:38]([CH3:39])([CH3:37])[C:6]=5[CH:7]=4)=[O:8])=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5c(c4)C(C)(C)CCC5(C)C)cc3)cc2C1=O
Yield: 76 %

Procedure:
The compound of example 175 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 5,5,8,8-tetramethyl-5,6,7,8-tetra hydronaphthalene-2-carbonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH:19]=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:29]1[CH:33]=[N:32][N:31]=[C:30]1[NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)CCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH2:19][NH:34][C:30]4[S:29][CH:33]=[N:32][N:31]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nncs1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: CC(C)(CNc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 18.5 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal (419 mg, 1.12 mmol) in ClCH2CH2Cl (20 mL) was added 1,3,4-thiadiazol-2-amine (137 mg, 1.35 mmol) and titanium tetraisopropoxide (0.35 mL, 1.2 mmol) at RT under nitrogen. The reaction mixture was heated at 85° C. for 1 hr then sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added and the reaction was heated at 85° C. for 4 hr. The reaction mixture was poured into a sat. sodium bicarbonate solution (100 mL), extracted with CH2Cl2 (100 mL), dried (Na2SO4) and concentrated. The final product was purified using HPLC to give 95 mg (19% yield) of N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropyl)-1,3,4-thiadiazol-2-amine which showed consistent 1H-NMR spectra. MS found: (M+H)+=458. NMR (CDCl3) δ 11.3 (bs, 1H); 8.12 (s, 1H); 8.03 (s, 1H); 7.82 (s, 1H); 7.52-7.55 (m, 2H); 7.48 (s, 1H); 7.39-7.41 (d, 2H); 7.11-7.23 (m, 5H); 4.16 (s, 1H), 3.09-3.18 (q, 2H); 1.18 (s, 6H).