Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1C=C(C=C[CH:9]=1)C=O.COCCl.[H-].[Na+].[Li]CCCC.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>CN(C=O)C.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.C([O-])([O-])=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[Cu+2]>[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:27]([CH:28]=[CH:2][CH3:9])[CH:26]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COCOc1cccc(C=O)c1
Agent: [Cu+2]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC=Cc1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (11.0 g, 90.1 mmol) in DMF (110 mL) at 0° C. was added methoxymethyl chloride (7.5 mL, 99.1 mmol) followed by NaH (99.1 mmol, 3.96 g, 60% dispersion in oil) in three portions (violent deprotonationl). The mixture was stirred at 0° C. for 15 min and then at room temperature for 15 h. The reaction was quenched with water and more water was added until all the precipitate dissolved. The solution was extracted in ether (2×150 mL) with water (50 mL), then with saturated Na2CO3 (100 mL), and finally with water (100 mL). The crude product was used in the next reaction. To a suspension of (ethyl)triphenylphosphonium bromide (36.8 g, 99.1 mmol, dried at 90° C. under high vacuum overnight) in THF (250 mL) at 0° C. was added n-BuLi (39.6 mL, 99.1 mmol, 2.5 M in hexanes) over five min. The resulting pretty dark burgundy mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. It was re-cooled to 0° C. and a solution of the above crude 3-methoxymethoxybenzaldehyde in THF (15 mL) was added slowly. The resulting medium brown mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was quenched by exposing it to air for several min. Because filtering the mixture for this particular Wittig reaction would result in a sticky precipitate clogging the sintered-glass filter, the THF was removed in vacuo and the crude material was dissolved in DMF (100 mL). Extraction in hexanes (4×100 mL) with 50% saturated brine (100 mL) eliminated triphenylphosphonium oxide into the aqueous layer. Flash chromatography with silica gel (gradient to 6% ether/hexanes) produced 1-(methoxymethoxy)-3-(1-propenyl)benzene [(E)/(Z)˜1:1] as a colorless liquid (13.2 g, 82% yield for two steps). A suspension of 3 produced 1-(methoxymethoxy)-3-(1-propenyl)benzene (13.2 g, 74.1 mmol), NaHCO3 (1.24 g, 14.8 mmol), and 10% palladium on carbon (3.3 g) in EtOAc (75 mL) and EtOH (19 mL) was stirred at room temperature for 20 h with a hydrogen balloon attached. The round-bottom flask was purged with nitrogen, the mixture was filtered through Celite, and the Celite was washed well with EtOAc to furnish 1-(methoxymethoxy)-3-propylbenzene as a colorless liquid (13.4 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.4 Hz), 1.64 (m, 2H), 2.56 (t, 2H, J=7.7 Hz), 3.48 (s, 3H), 5.17 (s, 2H), 6.80-6.90 (three overlapping peaks, 3H), 7.19 (m, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=2[N:22]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=2[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: OCc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2nc(OCc3ccccc3)ccc2C1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a solution of benzyl alcohol (0.18 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(benzyloxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.44 g, 71%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: C1CNCCN1
Reactant: CCOc1ccc2nc(Cl)sc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.36 mmol 2-chloro-6-ethoxy-benzothiazole (CA=[79071-17-3]), 3.00 mmol of piperazine and 3.00 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[C:1]([O:12][CH3:13])(=[O:11])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14]
Reactant: C=CCCCCCCCC(=O)OC
Agent: C=CC(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCC=CC(=O)OC
Temperature: 40 °C

Procedure:
10 g of methyl 9-decenoate (54 mmol) purified on alumina, 18.1 g of 3,3-dimethyl-1-butene (neohexene, 215 mmol, 4 equivalents) and 100 g of toluene are placed in a 250 ml 10 glass reactor purged with nitrogen. The mixture is heated at 40° C., followed by addition, over a period of 2 hours, of 3.4 mg of catalyst M73-SiPr supplied by the company Umicore (75 ppm mol) dissolved in 5 ml of toluene. At the end of the addition, the degree of conversion of the methyl decenoate, measured by CPG, is 86%. The selectivity toward cross metathesis product is 35%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[Si:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[OH:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: [Li]CCCC
Product: CN(C)S(=O)(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Yield: 57 %

Procedure:
The sulfonamide (97.45 g, 0.37 mol) was subsequently treated with n-butyllithium and 3-(tert-butyldimethylsilyloxy)benzaldehyde as described in Example 54, and the product was purified by chromatography on silica gel with hexane:ethyl acetate to give 89.5 g (57%) of 4-(3-(tert-butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide as a yellow oil which crystallized on standing. A portion was recrystallized from ethanol:water to give white crystals, mp 100°-103° C. NMR (CDCl3, 60 MHz): δ0.1 (s, 6H); 0.9 (s, 9H); 2.6 (s, 6H); 3.5 (br s, 1H); 5.7 (s, 1H); 6.5-7.7 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=1.C(NCC)C.CCCCCC.C([OH:35])C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][NH:12][CH2:13][C@@H:14]1[OH:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2Cl)CC1
Reactant: CCO
Solvent: CCNCC
Solvent: CCCCCC
Product: O[C@H]1CNCC[C@@H]1c1ccc(F)cc1Cl

Procedure:
3.62 g of the entitled compound was obtained as a pale orange solid from the latter fraction (retention time: 14.8 min) in the same method as in Production Example 25-3, for which, however, tert-butyl 4-(2-chloro-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate was used in place of tert-butyl 4-(2-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate used in Production Example 25-3, and an optically-active column (Daicel's CHRALPAK AD column, 2 cm×25 cm; 0.1% diethylamine, hexane/ethanol=9/1; flow rate, 20 mL/min) was sued for the optical resolution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O.[OH-].[Li+].Cl>CO.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC(N(CCNS(C)(=O)=O)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCNS(C)(=O)=O)[C@H]1CC[C@H](CC(=O)O)CC1
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl-[2-(methanesulfonamido)ethyl]amino]cyclohexyl]acetate (0.842 g, 2.06 mmol) in methanol (4 mL); THF (4 mL) and water (4 mL) was added lithium hydroxide monohydrate (252 mg, 6 mmol). The resulting solution was stirred for 2 hours then acidified with HCl (7 mL, 1M aq.), diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether to give the title compound as a solid.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.Cl.Cl.[N:38]1([CH:43]2[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:45]4[CH2:46][CH2:47][CH:43]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[CH2:44]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidin-yl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.24 (m, 2H), 2.06 (m, 4H), 1.85 (m, 2H), 1.74-1.56 (m, 3H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 508 [M+H]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32]>C(O)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C/c2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol), potassium carbonate (188 mg, 1.4 mmol) and 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124, 257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80° C. for 18 hours. The mixture was concentrated under reduced pressure, the residue taken up in dichloromethane (20 mL) and water (20 mL), the aqueous phase was back extracted with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 300 mg (69%) of product as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=2[Cl:1])=[C:6]([C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:7]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2Cl)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2Cl)c2cc[nH]c2c1=O

Procedure:
Example 34b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 34a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:21][C:11]3[C:10](=[O:13])[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3](=[O:14])[C:2]=3[N:1]=2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccc(Cl)cc3)nc21
Yield: 33.6 %

Procedure:
To a solution of 5.0 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 60 mL of dioxane, one adds at ambient temperature 15.3 mL (120 mmol) of 4-chlorobenzoic acid chloride and 0.5 mL of concentrated sulfuric acid. The reaction mixture is heated to reflux for 4 h, then evaporated to dryness, redissolved in 200 mL of dichloromethane, and neutralized at cold temperature with 100 mL of 10N sodium hydroxide. The organic phase is then washed three times with water and dried over calcium chloride. The red powder so obtained is purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 70/30). The yellow crystals obtained after evaporation of the solvent are uncolored and recrystallized in dichloromethane to produce 2.5 g of 2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][NH2:22])[N:16]2[N:23]=[CH:24][N:25]=[C:15]2[N:14]=1.O>CS(C)=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:22][CH2:21][CH2:20][NH:19][C:17]1[N:16]2[N:23]=[CH:24][N:25]=[C:15]2[N:14]=[C:13]([CH3:12])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1cc(NCCN)n2ncnc2n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCCNCC(O)COc2ccccc2)n2ncnc2n1
Reaction time: 48 h

Procedure:
3.6 g. Phenyl glycidyl ether and 9.0 g. 5-methyl-7-(2-aminoethylamino)-s-triazolo[1,5-a]pyrimidine are dissolved in dimethyl sulphoxide and left to stand for 48 hours at 45° C. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically in the manner described in Example 28. There are obtained 2.0 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 126°-127° C., after recrystallization from isopropyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4]([F:22])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:24])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4]([F:22])[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cc2F)c(F)c1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=S)Nc2ccc(Br)cc2F)c(F)c1
Yield: 48.1 %

Procedure:
Intermediate 32 (1 g, 2.56 mmol) dissolved in toluene (10 ml) and added P2S5 (0.57 g, 2.56 mmol). This mixture was refluxed for 18 h. Toluene removed on rotavapour to obtain the crude. Crude was purified by column chromatography on 60-120 mesh silicagel using EtOAc and Petether (20:80) as eluent to afford the title compound (500 mg) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.02 (s, 1H), 7.92-7.85 (m, 2H), 7.69 (dd, J 1.6, 8.1, 1H), 7.63 (dd, J 1.6, 9, 1H), 7.33-7.27 (m, 2H), 3.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]([S:19][CH3:20])[N:11]=2)[CH2:4]1.C[N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([NH2:22])=[O:17])=[CH:14][N:13]=[C:12]([S:19][CH3:20])[N:11]=2)[CH2:4]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(N)=O)C1
Yield: 95.4 %

Procedure:
4-((1R,3S)-3-Methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (1.1662 g, 3.92 mmol) and HATU (2.237 g, 5.88 mmol) were stirred in DMF (7.84 mL) for 5 min at room temperature, then ammonium chloride (1.049 g, 19.61 mmol) and DIEA (3.42 mL, 19.61 mmol) were added while stirring. The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The residual DMF was removed by suspending the oily residue in 100 mL water and 100 mL hexanes. The biphasic suspension was stirred vigorously for 30 min, filtered and washed with hexanes to afford 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (1.1081 g, 3.74 mmol, 95% yield) as an off-white solid. MS (ESI) m/z 397.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]([O:4][CH3:5])=[O:3].Cl.Cl.[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])[S:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C.O>CN(C)C=O.O1CCCC1>[ClH:1].[NH2:28][C:22](=[N:21][C:18]1[S:19][CH:20]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:2]([O:4][CH3:5])=[O:3])[CH:11]=2)[N:17]=1)[NH:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CN)c2)cs1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)OC)c2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
Methyl chloroformate (0.45 g) was added slowly to a suspension of 4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino] thiazole dihydrochloride (1.5 g) and triethylamine (1.6 g) in N,N-dimethylformamide (10 ml) and tetrahydrofuran (10 ml) with cooling on an ice bath. The mixture was stirred at room temperature for 8 hours. Water (100 ml) was added to the mixture. The mixture was extracted with a mixture of ethyl acetate (200 ml) and tetahydrofuran (20 ml). The extract was dried with magnesium sulfate and then evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1). The solvent was removed under reduced pressure and the residue was dissolved in ethanol (20 ml). 4N-Dioxane solution of hydrogen chloride (5 ml) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was crystallized from a mixture of ethanol and diisopropyl ether. Recrystallization from a mixture of ethanol and diisopropyl ether afforded 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-methoxycarbonylaminomethylphenyl)thiazole hydrochloride (0.43 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[CH3:1][N:2]([CH3:3])[C:5]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1Cl
Reactant: CNC
Product: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1N(C)C
Reaction time: 24 h

Procedure:
A solution of dimethylamine (5 mL of 2M in THF) was added to ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.9 mmol) and stirred in a sealed tube for 24 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give ethyl 2-(dimethylamino)-4-methyl-6-(trifluoromethyl)nicotinate as a colourless oil (450 mg): 1H NMR (500 MHz, CDCl3): δ 6.79 (1H, s), 4.39 (2H, q, J 7.1), 3.05 (6H, s), 2.32 (3H, s), 1.39 (3H, t, J 7.1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:58])[C@H:40]([CH2:54][C:55](=[O:57])[NH2:56])[NH:41][C:42]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1)=[O:43])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:21])[CH3:20])[NH:14][C:15]([O:17][CH3:18])=[O:16]>CN(C1C=CN=CC=1)C.O1CCOCC1.C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:58])[C@H:40]([CH2:54][C:55](=[O:57])[NH2:56])[NH:41][C:42]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1)=[O:43])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:20])[CH3:21])[NH:14][C:15]([O:17][CH3:18])=[O:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)O[C@@H](CN(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1

Procedure:
Under a nitrogen atmosphere, a small amount of DMAP and 0.2 ml of butyric acid chloride are added to a solution of 121 mg (0.17 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]-hydrazine (Example 109) in 3.5 ml of dioxane, 2 ml of methylene chloride and 0.4 ml of pyridine. Dilution of the reaction mixture with methylene chloride, washing with 2 portions of saturated NaHCO3 solution, water and brine, extraction of the aqueous phases with 2 portions of methylene chloride, drying of the organic phases with Na2SO4, concentration by evaporation and column chromatography (SiO2, methylene chloride/methanol 50:1→19:1) yields the title compound: TLC Rf (I')=0.5; tRet (V)=15.6 min.