Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]2[C:31]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=3)[CH:27]=[CH:26][CH:25]=[C:24]5[CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:34]1(B(O)O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCO.O>[C:34]1([C:2]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]3[C:31]4[C:32]5=[C:33]6[C:28](=[CH:29][CH:30]=4)[CH:27]=[CH:26][CH:25]=[C:24]6[CH:23]=[CH:22][C:21]5=[CH:20][CH:19]=3)=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)c1cc(-c2ccc3ccc4cccc5ccc2c3c45)c(C(=O)OCC)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc3ccc4cccc5ccc2c3c45)c(C(=O)OCC)cc1-c1cccc2ccccc12

Procedure:
43.5 g (90 mmol) of diethyl 2-chloro-5-pyren-1-ylterephthalate, 21.5 g (120 mmol) of 1-naphthylboronic acid and 58.1 g of Cs2CO3 are initially introduced in 230 ml of dry dioxane, and the mixture is saturated with N2 for 30 min. 2.7 ml of a 1.0 M solution of tri-tert-butylphosphine in toluene, followed by 300 mg (1.3 mmol) of Pd(OAc)2, are then added. The mixture is heated at the boil for 4 h and extended with water and EtOH, and the precipitate is filtered off with suction, washed with water and EtOH and dried. The solid is recrystallised three times from dioxane and then has a purity of >99% according to 1H-NMR. The yield is 44.2 g (90%) of colourless solid.
Reaction SMILES: [NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:31](O)=[O:32])[N:29]=1)=[O:23].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:31]([NH:1][CH:2]2[C:12](=[O:13])[N:4]3[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1)=[O:23]
Reactant: CCOCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 83.6 %

Procedure:
A solution of 7-amino-3-cephem-4-carboxylic acid (1.3 g.) and trimethylsilylacetamide (7.0 g.) in ethyl acetate (30 ml.) and a solution of 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetic acid (syn isomer, 1.72 g.), N,N-dimethylformamide (0.48 g.) and phosphoryl chloride (1.01 g.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.35 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:42])=[CH:25][C:26]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:29][CH2:28][C:27]=2[CH:41]=1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:42][C:24]2[C:23]([O:22][CH3:21])=[CH:41][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CCN1CCOCC1)CC2
Yield: 19 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a white foam (28 mg, 19%). MS (ESI+): 608 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.34 (d, J=8 Hz, 1H), 5.26 (d, 1H), 3.96 (m, 1H), 3.89 (s, 3H), 3.74 (t, 5 Hz, 4H), 3.27 (m, 1H), 2.90 9m, 4H), 2.80 (s, 3H), 2.71 (m, 6H), 2.59 (m, 2H), 2.57 (br s, 4H), 2.25 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:4]=2[N:3]=1.CO.O.[NH2:25]N>C(O)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[N:3]=[C:2]([NH:1][NH2:25])[CH2:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:5]=2[CH:17]=1
Reactant: COc1ccc(C2=NCC(N)=Nc3ccc(Cl)cc32)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3 parts of 2-amino-7-chloro-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine in a mixture of 50 parts by volume of methanol and 0.6 part by volume of glacial acetic acid is added dropwise with stirring 1.5 parts by volume of 100% hydrazine hydrate. The mixture is stirred for 30 minutes and poured into ice water, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene yields 7-chloro-2-hydrazino-5-(p-methoxypheyl)-3H-1,4-benzodiazepine as colorless crystals melting at 214° C to 220° C.
Reaction SMILES: CN.[CH2:3]([O:5][C:6](=[O:22])[CH:7]=[C:8]([NH:20][CH3:21])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:4].C([BH3-])#N.[Na+].Cl>C(O)C.C(O)(=O)C>[CH2:3]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:20][CH3:21])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:4]
Reactant: CCOC(=O)C=C(Cc1ccc2ccccc2c1)NC
Agent: CN
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(Cc1ccc2ccccc2c1)NC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2 ml (17.6 mmol) of a 27.3% solution of methylamine in ethanol and 5.5 ml of acetic acid are added to 24.9 g (92.5 mmol) of 3-methylamino-4-(2-naphthyl)-but-2-enoic acid ethyl ester in 250 ml of ethanol and the mixture is cooled to 0° C. 6.4 g (87 mmol) of 85% sodium cyanoborohydride and a further 5.5 ml of acetic acid are added to the suspension. The reaction mixture is allowed to rise to room temperature, with stirring, over a period of 2 hours. A further 0.64 g (8.7 mmol) of sodium cyanoborohydride is added to the clear solution and stirring is continued at room temperature for a further 2 hours. 400 ml of 1N hydrochloric acid are then added and the reaction mixture is stirred for 1 hour and then the ethanol is evaporated off in a rotary evaporator. The aqueous phase is washed twice with ether and the ether phases are extracted with 1N hydrochloric acid. Ethyl acetate is added to the combined aqueous phases and the mixture is rendered basic with solid potassium carbonate; the organic phase is separated off and washed with brine. The title compound is obtained in the form of a slightly brown oil. IR: 1725 cm-1 ; 1H-NMR, 200 MHz, CDCl3, delta, (ppm): 7.86-7.32 (m, 7H), 4.12 (q, 2H), 3.26 (quint., 1H), 3.05-2.82 (ABxd, 2H), 2.53-2.44 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][O:15]C)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:17]>O1CCCC1>[F:17][C:3]1[CH:4]=[C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC=C1CCC(c2ccc(F)c(F)c2)CC1
Solvent: C1CCOC1
Product: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.6 g of 1,2-difluoro-4-[4-(methoxymethylidene)cyclohexyl]benzene in 125 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to 90° C. for 1.25 hours. The reaction mixture was subsequently poured on to ice-water and extracted with diethyl ether. The ether phase was washed neutral with 50 ml of semi-saturated sodium hydrogen carbonate solution and with two 50 ml portions of water, dried over sodium sulphate and concentrated. A solution of the resulting crude trans/cis mixture (5.1 g) in 25 ml of methanol was added dropwise in an inert gas atmosphere at 0°-3° C. within 5 minutes to 70 ml of 0.1N methanolic potassium hydroxide solution. The reaction mixture was stirred at 0° C. for 1 hour, then poured on to 200 ml of ice-water and extracted with diethyl ether. The ether phases were washed neutral with water, dried over sodium sulphate and concentrated. There were obtained 4.8 g of trans-4-(3,4-difluorophenyl)cyclohexanecarboxaldehyde (cis content 5.7%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC=CC=1CCl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1Cl
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chlorobenzyl chloride (available from Aldrich Chemical Company) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=408 and 410.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]([C:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]([CH:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1C(=CCCCC(=O)O)c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1C(CCCCC(=O)O)c1cccnc1

Procedure:
A mixture of 2.36 g of 6-(5-(2-(4-fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hex-5-enoic acid, 0.4 g of sodium hydroxide and 1 g of 10% palladium/charcoal in 50 ml of methanol is hydrogenated under 5 bar of hydrogen pressure. Then the catalyst is filtered off, the filtrate is evaporated down, the residue is diluted with water, acidified and extracted with ethylene chloride. The organic extract is evaporated down and the residue recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13].ClC1C(C(F)(F)F)=CC=CC=1C(N1C=CC2N(C3C=NC=CN=3)N=NC=2C1C)=O>>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13]
Reactant: Cc1ccnc(-n2nnc3c2C=CN(C(=O)c2cccc(C(F)(F)F)c2Cl)C3C)n1
Agent: CC1c2nnn(-c3cnccn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Product: Cc1ccnc(-n2nnc3c2CCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C3C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 73 substituting the product of Example 252, Step 2 for the 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-methyl-1-pyrazin-2-yl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (E S I) mass calcd. C19H16ClF3N6O, 436.1. m/z found, 437.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37][CH:38]([F:58])[O:39][C:40]1[N:41]=[CH:42][CH:43]=[C:44]2[C:49](=[O:50])[C:48](I)=[C:47]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:46][C:45]=12>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:48]3[C:49](=[O:50])[C:44]4[C:45]([O:46][C:47]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[C:40]([O:39][CH:38]([F:58])[F:37])[N:41]=[CH:42][CH:43]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(OC(F)F)nccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OC(F)F)nccc4c3=O)cc2)CCC1
Yield: 56 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-difluoromethoxy-3-iodo-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound as a colourless oil (24 mg, 56%). LCMS (Method A): RT=4.85 min, [M+H]+=535.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:14][CH2:15][CH2:16][Cl:17])=[O:13])[CH2:10][CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.[OH2:26]>C(O)(=O)C.C(OO)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:14][CH2:15][CH2:16][Cl:17])=[O:13])[CH2:10][CH2:9][N+:8]([O-:26])=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: O
Reactant: O=C(NCCCl)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: O=C(NCCCl)N1CC[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
10 Parts of 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide is dissolved in 50 parts by volume of glacial acetic acid and to this solution 10 parts by volume of 40% peracetic acid is added all at once with stirring. The reaction mixture is stirred at ambient temperature for about 24 hours and then slowly poured into 1000 parts by volume of cold water. The precipitate which forms is extracted with methylene chloride, the extract dried over magnesium sulfate and the solvent removed. The residue crystallizes from ethanol to afford 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide 4-oxide. This compound is represented by the following formula ##STR37##
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[OH-].[Ca+2:32].[OH-].CCCCCCC>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[Ca:32]
Reactant: [Ca+2]
Agent: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC(C)O
Product: [Ca]
Temperature: 25 °C

Procedure:
To 40.81 g losartan of Example 1 in 235 ml i-propanol, 3.92 g calcium hydroxide were added, and it was stirred at reflux temperature for 1 hour, and hot filtered. 410 ml n-heptane were added to the filtrate and cooled to room temperature. The solvent was decanted from a resinous residue, and 820 ml n-heptane were added. It was stirred until a white solid crystallized. It was filtered, washed with 110 ml n-heptane, and dried in vacuo at 50° C. to yield 39.2 g losartan calcium.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([O:23]C)[CH:17]=[C:16]([O:25]C)[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([OH:23])[CH:17]=[C:16]([OH:25])[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(NC(C)C)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)Nc1cccc(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1Cl

Procedure:
A mixture of example 64 (0.900 g, 1.98 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: C(OC(NC(C)(CC1C=CC=CC=1)COCC1C=C(C=C(N(S(C)(=O)=O)CCC)C=1)C(O)=O)=O)(C)(C)C.CC(N)C#CC.[NH2:44][C:45]([CH3:83])([CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[CH2:46][O:47][CH2:48][C:49]1[CH:50]=[C:51]([N:68]([CH2:73][CH2:74][CH3:75])[S:69]([CH3:72])(=[O:71])=[O:70])[CH:52]=[C:53]([C:55]([N:57]2[CH2:61][CH2:60][CH2:59][CH:58]2[C:62]2C=CC=CC=2)=[O:56])[CH:54]=1>>[NH2:44][C:45]([CH3:83])([CH2:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[C:53]([CH:52]=[C:51]([N:68]([S:69]([CH3:72])(=[O:71])=[O:70])[CH2:73][CH2:74][CH3:75])[CH:50]=1)[C:55]([NH:57][CH:58]([CH3:62])[C:59]#[C:60][CH3:61])=[O:56]
Reactant: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)N2CCCC2c2ccccc2)c1)S(C)(=O)=O
Agent: CC#CC(C)N
Agent: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Product: CC#CC(C)NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(CCC)S(C)(=O)=O)c1

Procedure:
3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-(1-methylbut-2-yn-1-yl)-5-[(methylsulfonyl)(propyl)amino]benzamide was prepared from 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI) and (1-methylbut-2-yn-1-yl)amine (intermediate XIII) following a similar procedure as described for the preparation of N-{3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(2-phenylpyrrolidin-1-yl)carbonyl]phenyl}-N-propylmethanesulfonamide. HRMS (ES, M+H) calculated for C27H37N3O4S: 500.2578, found: 500.2595.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)[N:9]=1)[CH3:1]
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)cn1

Procedure:
Following the procedure of Example 1, 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.54 g. of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone were dissolved in 50 ml. of ethanol and the resulting solution heated at reflux temperature for about 1 week. The solvent was removed by evaporation and the residue purified by gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing the desired pyrimidone were combined and the solvents removed from the combined fractions. The resulting residue was crystallized from ethyl acetate to yield 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methoxy-3-pyridyl)methyl-4-pyrimidone melting at 137°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][C:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH:20]=3)[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pt].CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CC=C(CC2(c3cccc(OC)c3)OCCO2)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(CC2(c3cccc(OC)c3)OCCO2)CC1

Procedure:
A mixture of 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1(6H)-pyridinecarboxylate and 450 parts of methylbenzene is hydrogenated at normal pressure and at room temperature with 4 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of ethyl 4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1-piperidinecarboxylate as a residue.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[CH:24]=[CH:25][C:26](Cl)=[CH:27][C:22]4=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:36][CH2:37][CH2:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])(C)(C)C>>[NH2:36][CH2:37][CH2:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:26]2[CH:25]=[CH:24][N:23]3[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=5)=[O:29])=[CH:14][CH:15]=4)=[CH:20][N:21]=[C:22]3[CH:27]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Cc2ccc(-c3cnc4cc(Cl)ccn34)cc2)no1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccc(S(=O)(=O)CCN)cc5)ccn34)cc2)no1
Yield: 80.7 %

Procedure:
Couple N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide (0.700 g, 1.71 mmol) to {2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-ethyl}-carbamic acid tert-butyl ester (0.775 g, 1.88 mmol) using procedure similar to Example 115. Treat the crude extracts to SCX ion exchange chromatography during which time some of the BOC-group is cleaved. Elute from the SCX column and treat with 2N HCl in dioxane (125 mL) and 10 mL of methanol for 2 hours. Evaporate in vacuo to provide the intermediate (0.87 g, 1.38 mmol). MS(ES), m/z 616 (M+1).
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[CH:33]([CH3:38])[C:34]([O:36][CH3:37])=[O:35])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]>[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[CH:33]([CH3:38])[C:34]([O:36][CH3:37])=[O:35])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)c1cc(Cl)ccc1C1=CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Agent: [Pt]
Solvent: CCO
Product: COC(=O)C(C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 15 h
Yield: 90.4 %

Procedure:
A mixture of methyl 2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorophenyl]propanoate (2-4) (1.92 mmol) and platinum (TV) oxide (0.350 g) in ethanol/glacial acetic acid (1:1, 20 mL) was hydrogenated at atmospheric pressure for approximately 15 h. The resulting mixture was filtered through a short column of celite®, eluted copiously with ethanol. The filtrate was evaporated and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase was re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (Na2SO4), and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-15% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished 2-5 (0.95 g) as a colorless foam (m/z (ES) 547 (MH+).