Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:53].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[I:20])[CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[NH:50][CH2:51][C:52](=[O:53])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)O
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-chloro-4-iodophenyl)propanoic acid (4.16 g, 9.77 mmol) in DMF (80 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.6 g, 10.0 mmol). After 10 minutes at rt the solution was treated with a solution of 2-amino-1-phenylethanone hydrochloride (2.52 g, 14.6 mmol) and N,N-diisopropylethylamine (8.5 mL, 49.0 mmol). The solution was stirred at rt for 2 h. The solution was diluted with ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate solution (200 mL). The organic phase was dried over sodium sulfate. Purification by silica gel chromatography (5–25% ethyl acetate:hexanes) afforded product as a white solid (3.1 g, 58%). LCMS found for C22H25ClIN2NaO4 (M+Na)+: m/z=565.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (450 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (480 mg, 1.8 mmol, Amine-61, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN1C(=O)N(C)CCC1.Br[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g (25.2 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 400 ml THF was treated at −78° C. with 33.0 ml (68.3 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h, then 27.8 ml (230.4 mmol) of DMPU were added and 10 min later 19.0 ml (125.9 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran dissolved in 20 ml were dropped in during 20 min. The reaction was warmed up to RT and stirred over night (approx. 16 h). An aqueous solution of saturated NH4Cl was added and the mixture was extracted with ether (3×). The organic phase was washed with H2O (2×), aqueous 10% NaCl and dried with Na2SO4, filtered and evaporated to give after flash column chromatography on silica gel (Hexane/EtOAc 19:1 to 3:1) 3.5 g (38%) of trans-Methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 366 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:12](=[O:13])[N:11]2[C@@H:7]1[CH2:8][C:9]([S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])([CH3:5])[CH3:4].P([O-])([O-])(O)=O.[K+:39].[K+].O.C(O)C>O1CCOCC1.[Pt](=O)=O>[CH3:1][O:2][C:3]([C@H:6]1[C:12](=[O:13])[N:11]2[C@@H:7]1[CH2:8][C:9]([S:27][C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)=[C:10]2[C:14]([O-:16])=[O:15])([CH3:5])[CH3:4].[K+:39]
Reactant: COC(C)(C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COC(C)(C)[C@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccncc3)C[C@H]12
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzyl (5R, 6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (371.0 mg) and platinum (IV) oxide (123.7 mg) in a mixture of dioxane (44.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (23.7 ml), water (5.98 ml) and ethanol (3.71 ml) was shaken for an hour under a hydrogen atmosphere (50 psi) at ambient temperature. The reaction mixture was filtered using super cell. The filter cake was washed with water, and the combined filtrates were concentrated. The residual aqueous layer was washed three times with diethyl ether at 0° C. and concentrated. After addition of potassium chloride (9 g), the resultant aqueous solution (180 ml) was chromatographed on non-ionic adsorption resin "Diaion HP-20 AG" (24×300 mm) eluting successively with water (420 ml), 5% aqueous isopropyl alcohol (420 ml) and 10% aqueous isopropyl alcohol (420 ml). The fractions, whose UV spectrum showed λ max 303 nm, were collected, concentrated and lyophilized to give potassium (5R, 6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (208.7 mg) as a white powder.
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8](O)[SiH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>>[CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([Br:35])[SiH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C(O)[SiH](C)C)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1ccc(C(Br)[SiH](C)C)cc1

Procedure:
Reaction of 4-allyldimethylsilylbenzyl alcohol (3 Scheme 1) with triphenylphosphine and carbon tetrabromide gave 4-allyldimethylsilylbenzyl bromide (4 Scheme 13). Subsequent reaction with potassium cyanide gave 4-allyldimethylsilylphenylacetonitrile (6 Scheme 13). Under the usual coupling conditions, this was loaded to the polymer and the loading level of resin (2 Scheme 13, 0.23 mequiv/g) was determined by the mass balance of 4-bromophenylacetonitrile which was obtained from cleavage reaction of the resin with bromine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.O1CCOCC1.[Pd]>[CH:33]([C@H:30]1[C@@H:21]2[C@@H:22]3[C@@:17]([CH3:46])([CH2:18][CH2:19][C@@:20]2([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)[C@@:16]1([CH3:47])[C@@H:25]([C@:26]2([CH3:29])[C@@H:13]([CH2:14][CH2:15]1)[C:12]([CH3:49])([CH3:48])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:28][CH2:27]2)[CH2:24][CH2:23]3)([CH3:35])[CH3:34]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (0.2 g, 0.302 mmol) in ethanol (5 mL), 1,4-dioxane (7 mL), and acetic acid (0.5 mL, 8.73 mmol) was added Pd/C (10% by wt.) (0.1 g, 0.094 mmol). The mixture was flushed with N2 and was put on the Parr shaker under 30 psi H2. After 2 h, the reaction was checked by 1H NMR. The benzyl group had been removed, but the alkene still remained. The mixture was again flushed with N2. An additional 50 mg of 10% Pd/C was added and the mixture was pressurized to 40 psi H2. After stirring the mixture overnight, it reaction was removed from the Parr shaker and the palladium catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give the expected product, (1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.174 g, 100% yield), as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.91 (d, J=8.24 Hz, 2H), 7.22 (d, J=8.55 Hz, 2H), 3.89 (s, 3H), 2.39 (dd, J=13.12, 3.05 Hz, 1H), 2.19-2.29 (m, 3H), 2.01-2.13 (m, 1H), 0.99 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.86 (d, J=6.71 Hz, 3H), 0.79-1.92 (m, 22H), 0.76 (d, J=6.71 Hz, 3H), 0.75 (s, 3H), 0.68 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>CN(C=O)C.C1(C)C=CC=CC=1>[ClH:24].[Cl:24][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=c1[nH]cnc2cc(OCCCN3CCOCC3)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1ncnc2cc(OCCCN3CCOCC3)ccc12
Yield: 100 %

Procedure:
A mixture of 7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (200 mg, 0.69 mmol) in thionyl chloride (5 ml) and DMF (0.1 ml) was heated at reflux for 1 hour. The solution was diluted with toluene and the volatiles removed by evaporation. The residue was dissolved in methylene chloride and ether was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-7-(3-morpholinopropoxy)quinazoline hydrochloride (238 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.CN1CC2C=CC=CC=2NCC1>>[BrH:1].[Br:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CC(=O)Nc2ncc(Br)cc2C1
Agent: CN1CCNc2ccccc2C1
Product: Br
Product: CN1CCNc2ncc(Br)cc2C1

Procedure:
7-bromo-4-methyl-1,3,4,5-tetrahydro-pyrido[e][1,4]diazepin-2-one (1.67 g, 6.55 mmol) was reduced to give a 1:1 mixture of the title compound and 4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. The mixture was dissolved in acetic acid (12 mL), treated with bromine (1.04 g, 6.5 mmol) and stirred at room temperature overnight. Ether (100 mL) was added and the precipitate was isolated by filtration to yield the title compound as an orange solid (2.04 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ10.23 (s, 1H) 8.16 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 6.89 (s, 1H), 4.25-4.48 (m, 2H), 3.54-3.58 (m, 2H), 3.28-3.35 (m, 2H), 2.86-2.87 (m, 3H); MS (ESI) m/e 242 (C9H12BrN3+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:31]#[N:32])[CH2:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Na+].[CH3:34][S:35]([O-])(=[O:37])=[O:36]>CS(C)=O.CCOC(C)=O.[Cu](I)I>[C:31]([C@@H:22]([NH:21][C:19](=[O:20])[C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:26][CH:25]=1)#[N:32]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Reactant: CS(=O)(=O)[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]-L-leucinamide (1 eq) in DMSO (0.3 M) were added methane sulfonic acid sodium salt (2 eq) and copper iodide (3 eq) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with brine and water, dried over Na2SO4, filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:34])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([CH:14]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:34])[NH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: Cc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C(CCCc1ccccc1)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
270 mg (2.14 mmol) of oxalyl chloride in 10 ml of dichloromethane are treated dropwise at −70° C. with 360 mg (4.64 mmol) of dimethyl sulphoxide. The mixture is stirred at −70° C. for 30 min, then 800 mg (1.78 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide are added. After a further 30 min, during which the temperature in the batch rises to about −60° C., 900 mg (8.92 mmol) of triethylamine are added and the cooling bath is then removed. If the batch temperature has warmed almost to room temperature, 10 ml of water are added and, after stirring briefly, the phases are separated. The dried organic phase is chromatographed in dichloromethane/methanol 50/1.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([P:34](=[O:36])=[O:35])[N:3]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][NH:22][C:23]2[C:28](Cl)=[C:27](Cl)[N:26]=[C:25](Cl)[C:24]=2Cl)[CH:16]=[C:15]([CH3:33])[CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C>CO.[Pd]>[CH3:1][C:2]([CH3:37])([P:34](=[O:36])=[O:35])[N:3]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[C:15]([CH3:33])[CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: Cc1cc(OCCNc2c(Cl)c(Cl)nc(Cl)c2Cl)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(OCCNc2ccncc2)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2)c1

Procedure:
0.2 g (0.33 mmol) N-(dimethyloxophosphinyl-methyl)-N-{3-methyl-5-[2-(2,3,5,6-tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-benzenesulfonamide in 10 ml methanol was hydrogenated in the presence of 0.28 ml triethylamine and 0.1 g 10% palladium on carbon at room temperature and normal pressure. After 18 hours it was filtered, the residue was dissolved in 3 ml ethanol, 30 ml ether was added, it was filtered, washed with ether and 0.12 g (77%) of the title compound of Fp. 228°-232° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:37]=[C:36]([F:38])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH2:32][CH2:33][S:34][CH3:35])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:39])[CH:5]=1)[CH3:2].ClC1C=CC=CC=1C(OO)=[O:48].ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:39])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:21]([O:31][CH2:32][CH2:33][S:34]([CH3:35])=[O:48])=[CH:20][N:19]=3)=[N:10]2)=[C:36]([F:38])[CH:37]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: O=C(OO)c1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1.24 g 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (4-16, 2.26 mmol, 1. eq.) in 2.15 ml of dry chloroform, was added slowly at 0° C. a solution of 557 mg 2-chlorobenzenecarboperoxoic acid (77%, 2.49 mmol, 1.1 eq.) in 2.15 ml chloroform. After 30 min dichloromethane and sodium thiosulfate-solution (10%) were added. The slurry was stirred for 5 min. After separating the solid (product) the aqueous layer was washed with dichloromethane twice. The organic layers were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography and combined the former isolated solid to yield 1.22 g (2.05 mmol, 91%) of the analytically pure target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[N:19]=[C:18](N3CCOCC3)[N:17]=[C:16]([O:26][CH2:27][CH2:28][O:29]C(=O)NC3C=CC=CN=3)[C:15]=2[O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[Cl-].[NH4+:49].[N-:50]=[N+:51]=[N-:52].[Na+]>>[OH:29][CH2:28][CH2:27][O:26][C:16]1[N:17]=[C:18]([C:4]2[CH:1]=[CH:2][N:49]=[C:6]([C:7]3[NH:8][N:52]=[N:51][N:50]=3)[CH:5]=2)[N:19]=[C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)(=[O:12])=[O:11])[C:15]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(N2CCOCC2)nc1OCCOC(=O)Nc1ccccn1
Reactant: [N-]=[N+]=[N-]
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1OCCO

Procedure:
reacting the product of step f) with ammonium chloride and sodium azide to form 5-isopropyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH:5]=1.C([Mg]Br)C.C(O[C@H:22]1[NH:25][C:24](=[O:26])[C@@H:23]1[C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])(=O)C.Cl>O1CCCC1.C(OCCCC)(=O)C>[Si:30]([O:29][C@@H:27]([C@@H:23]1[C@@H:22]([C@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C:4]2=[O:3])[NH:25][C:24]1=[O:26])[CH3:28])([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CO[C@H]1CCCC=C1O[Si](C)(C)C
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCOC(C)=O
Product: CO[C@H]1CCC[C@H]([C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To a solution of 1-trimethylsilyloxy-6-(S)-methoxy-1-cyclohexene (800 mg, 4 mmol) in tetrahydrofuran (5 ml), a tetrahydrofuran solution containing 1 mol/liter of ethylmagnesium bromide was added and stirred at room temperature for 3 days. This mixture was then cooled to 0° C., and a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl)-2-azetidinone (861 mg, 3 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture and stirred at 0° C. for 1 hour. The resultant mixture was subjected to addition of 2N hydrochloric acid and extraction with butyl acetate. The organic phase was washed with a saturated sodium hydrogencarbonate solution and water, and concentrated under a reduced pressure to obtain a crude product of (3S,4R)-3-[(R)-1-((tert-butyldimethylsilyl)oxy)ethyl]-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]azetidin-2-one. The crude product contained 170 mg of the objective β-isomer. The yield was 16%, and the β:α ratio was 90:10.
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 hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[NH:20][N:19]=[N:18][CH:17]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([C:42](=O)[CH2:43][CH2:44][CH3:45])[C:37](OCC)=[O:38])=[CH:31][CH:30]=1)#[N:22].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:37](=[O:38])[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([C:24]4[C:23]([C:21]#[N:22])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:30][CH:31]=3)=[C:42]([CH2:43][CH2:44][CH3:45])[N:20]3[N:19]=[N:18][CH:17]=[C:16]23)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnn[nH]2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2cnnn12

Procedure:
N-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine (5.55 g) and a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (13.07 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.85 g) in N,N-diethylaniline (30 mL) were stirred at 185° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=90/10→80/20 (volume ratio)] to give the title compound as a brown amorphous compound (1.58 g, 15%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][N:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:14])=[O:13])[CH3:10]>>[CH3:10][N:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])(=[O:14])=[O:13])[CH3:8]
Reactant: CN(C)NS(=O)(=O)c1ccccc1O
Reactant: O=C=NS(=O)(=O)Cl
Product: CN(C)NS(=O)(=O)c1ccccc1OS(=O)(=O)N=C=O

Procedure:
To 5.2 ml (0.06 mole) chlorosulfonyl isocyanate in 75 ml dry xylenes was added 10.1 g (0.05 mole) of 2-(dimethylaminosulfamoyl)phenol in 15 ml xylenes, keeping the reaction temperature <5° C. This mixture was then heated to reflux temperature for 1 hour. The reaction solution was then cooled and the solvent evaporated to give an oil. The infrared spectrum showed NCO absorption at 2270 cm-1.