Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 70 °C
Yield: 78.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) in MeOH (30 mL) and dioxane (30 mL) was added 1N NaOH aq solution (27.1 mL). The mixture was heated at 70° C. for 1.5 hour and diluted with water (120 mL) and washed with ether. The pH value of aqueous phase was adjusted to 5.5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) as pale yellow powder.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1>Cl>[ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(CCc1ccc(C=NN)cc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCOC(=O)C(CCc1ccc(C=NN)cc1)(CC(=O)O)C(=O)OCC
Reaction time: 8 h

Procedure:
11.34 g of ethyl 4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyrate hydrochloride are stirred in 250 ml of 6N HCl at 40° C. for 1 h and at 80° C. for 2 h. The mixture is then allowed to stand overnight at room temperature and is concentrated to dryness in vacuo. The residue is taken up in a little water and freeze-dried.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([NH2:12])=[O:11])[CH:2]=1.[N:13]1[N:17]2[CH:18]=[CH:19][CH2:20][NH:21][C:16]2=[C:15]([C:22]([NH2:24])=[O:23])[CH:14]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[N:12][C:10]([C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=12)=[O:11])[CH3:29].[CH3:27][N:28]([CH:30]=[N:24][C:22]([C:15]1[CH:14]=[N:13][N:17]2[CH:18]=[CH:19][CH2:20][NH:21][C:16]=12)=[O:23])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cnn2cccnc12
Reactant: NC(=O)c1cnn2c1NCC=C2
Product: CN(C)C=NC(=O)c1cnn2c1NCC=C2
Product: CN(C)C=NC(=O)c1cnn2cccnc12

Procedure:
Other N-((dimethylamino)methylene)pyrazolo (1,5-a)-pyrimidine-3-carboxamide and N-((dimethylamino) methylene)-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide products which are prepared from corresponding pyrazolo(1,5-a)pyrimidine-3-carboxamide or the 4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide intermediate compounds by heating with N,N-dimethylformamide dimethyl acetal in the manner described in Examples 20-22 are listed in Table IX.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CO.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
100 Milliliters of 20% hydrous pyridine was added to 3.16 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 2.94 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol and 4.54 g of DCC, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF. The resulting solution was added dropwise to 500 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. To the collected precipitate was added 150 ml of methanol to dissolve the precipitate. To the solution was added 3 g of active carbon, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 30 ml of methanol to dissolve the residue with heating. The resulting solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.5 g of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([O:32]C)=[O:31])=[CH:22][N:21]=3)[C@H:16]([CH3:34])[CH2:15]2)=[C:10]([CH3:35])[C:9]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=3)[C@H:16]([CH3:34])[CH2:15]2)=[C:10]([CH3:35])[C:9]=1[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)[C@H](C)C2)c1C
Temperature: 75 °C
Yield: 96.6 %

Procedure:
To a solution of methyl 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylate (500 mg, 1.0 mmol, 1.0 eq) in THF (5 mL) is added an aqueous solution of LiOH (1 M, 2.0 mL, 2.0 mmol, 2.0 eq) and the resulting solution is heated to 75° C. for 4 h. The reaction mixture is diluted with EtOAc (50 mL) and washed with water (3×15 mL). The combined aqueous washes were adjusted to pH 6 with aqueous HCl (1 M), then extracted with dichloromethane (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to yield the desired product as a white solid (470 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][C:22]3[O:25][CH:26]=[CH:27][C:21]=3[CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:26]1[O:25][C:22]2[CH2:23][CH2:24][N:19]([S:16]([C:13]3[CH:12]=[CH:11][C:10](/[CH:9]=[CH:8]\[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:15][CH:14]=3)(=[O:18])=[O:17])[CH2:20][C:21]=2[CH:27]=1)[CH3:30]
Reactant: C=O
Reactant: O=S(=O)(c1ccc(/C=C\c2ccccc2Cl)cc1)N1CCc2occc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(/C=C\c3ccccc3Cl)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.582 g (1.458 mmol) of (Z)-5-(2-chlorostilbene-4'-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.20 g (2.19 mmol) of 50% aqueous dimethylamine and 0.18 g (2.19 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[C:38]([CH3:43])[CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[C:38]([CH3:43])[CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: Cc1cccc2c1CCC2N
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3c(C)cccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-4-methyl-indane
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([NH:23][C:24]([NH2:26])=[NH:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O>CN(C=O)C>[NH2:26][C:24]1[N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:25]=1
Reactant: O=C(CBr)CCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2ccccc2)nc1N
Reaction time: 48 h
Yield: 63 %

Procedure:
1-bromo-7-phenylheptan-2-one (1.00 g, 3.71 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (1.77 g, 11.13 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.77 g, 63% yield), 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 2H), δ 7.26 (m, 3H), δ 6.66 (s, 2H), δ 6.51 (s, 1H), δ 2.63 (t, J=7.5 Hz, 2H), δ 2.39 (t, J=7.5 Hz, 2H), δ 1.67 (m, 4H), δ 1.53 (s, 9H), δ 1.40 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.8, 143.0, 130.3, 128.7, 128.5, 125.8, 106.2, 84.5, 36.1, 31.6, 29.2, 28.5, 28.4, 28.2 ppm; IR νmax (cm−1) 3433, 2098, 1639, 1454, 1204; HRMS (ESI) calcd for C19H27N3O2 (M+) 329.2103, found 329.2109. Then, tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated de vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.62 g, 63% overall yield). 1H NMR (300 MHz, CD3OD) δ 7.20 (t, J=7.2 Hz, 2H), δ 7.12 (d, J=7.2 Hz, 3H), δ 6.37 (s, 1H), δ 2.56 (t, J=7.5 Hz, 2H), δ 2.41 (t, J=7.5 Hz, 2H), δ 1.57 (m, 4H), δ 1.34 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 147.3, 142.5, 128.3, 128.1, 127.7, 125.6, 108.2, 35.5, 31.1, 28.3, 27.0, 24.2 ppm; IR νmax (cm−1) 3385, 2933, 2857, 1679, 1536, 1495, 1453, 1335, 1172, 748, 700; HRMS (ESI) calcd for C14H19N3(M+) 229.1578, found 229.1571.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClCCl>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C#CCCn1ccnn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ncc(C#CCCn2ccnn2)cn1
Reaction time: 4 h

Procedure:
5-Bromo-2-chloro-pyrimidine (0.500 g, 2.53 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.368 g, 3.03 mmol) and triethyl amine (NEt3) (5.0 ml) are dissolved in DMF (10 ml) and copper iodide (CuI) (0.052 g, 0.27 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium(0) (0.149 g, 0.13 mmol) is added and stirring is continued for 4 h at 80° C. Dichloromethane (125 ml) is added, the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 4:1) yielding 2-chloro-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine as a colorless solid. Yield 373 mg (63%).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]O)[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:42][CH2:43][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:40][CH2:41]1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COc1ccccc1N1CCN(CCO)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCOC(=O)C23CC4CC(CC2C4)C3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (0.6 g, 3.6×10-3 mol) in 25 ml of chloroform un der a dry nitrogen atmosphere was added carbonyldiimidazole (0.58 g, 3.6×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 2-[1-(2-methoxyphenyl)-4-piperazinyl]ethanol (0.86 g, 3.6×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, RF=0.60) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (0.82 g, 44% yield), mp.=207°-208° C.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH:26]([CH3:28])[CH3:27])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.S(Cl)([Cl:31])=O.O1CCCC1>CN(C)C=O.O>[Cl:31][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH:26]([CH3:28])[CH3:27])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1
Reactant: CC(C)N(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-isopropylthiophene-2-sulfonamide (2.12 g), thionyl chloride (0.70 ml), N,N-dimethylformamide (two drop) and tetrahydrofuran (30 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, aqueous sodium bicarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from diethyl ether, and the crystals were collected by filtration, washed with diethyl ether, and dried to give the title compound (2.00 g, yield 90%) as yellow crystals. melting point 184-185° C.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:28][C:29](=[NH:31])[CH3:30]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:31]=[C:29]([CH3:30])[N:28]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (1.01 g, 5.00 mmol) in 2 mL of DMF was added carbonyldiimidazole (0.812 g, 5.01 mmol). This reaction mixture was stirred at room temperature for 6 h. N-Hydroxy-acetamidine (0.374 g, 5.05 mmol) was added. This reaction mixture was stirred at room temperature for 2 h then heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration was washed with acetonitrile and water, air-dried to give [1-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester as 1.05 g of white solid, m/z 240 [M+1]+. [1-(3-Methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester (80 mg, 0.33 mmol) was dissolved in HCl in 1,4-dioxane (4.0 M, 1.0 mL, 4.0 mmol). After standing at room temperature for 1 h, the solvent was removed by a stream of nitrogen. The title compound was isolated and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[I:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Yield: 102.3 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (25 g, 95.05 mmol) and triphosgene (77.1 g, 260.4 mmol) in dioxane (316 mL) was heated to reflux for 8 h. The resulting solid was filtered and washed with diethyl ether to give 28.1 g of the title compound, 1H NMR (300 MHz, Me2SO-d6): δ6.96 (d,1H); 8.02 (dd,1H); 8.13 (d,1H); 11.82 (br s,1H); m/e 288 deprotonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode (APCI-).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=3)[CH:8]=2)[O:3]1.[C:25](O)(=[O:27])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:25](=[O:27])[CH3:26])=[CH:18][N:17]=3)[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc2O1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1

Procedure:
A solution of 3.09 g (10 mmol) of 2,2,4,4-tetramethyl-6-[2-(5-hydroxymethylpyrid-2-yl)ethynyl]chroman (Compound 50) 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is then filtered and the residue washed with 50 ml of methlene chloride. The filtrate is then concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:37])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:35][CH3:36])[CH:10]=1)=[O:8])=O)C>ClCCl.CO>[CH3:34][C:30]1[CH:29]=[C:28]([NH:27][C:21]2[C:20]3[C:25](=[CH:26][C:17]([O:16][CH2:15][C:11]4[CH:10]=[C:9]([S:7]([CH3:37])(=[NH:6])=[O:8])[CH:14]=[CH:13][CH:12]=4)=[C:18]([O:35][CH3:36])[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccnc(C)c3)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Yield: 79 %

Procedure:
According to GWP 6, conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-4-pyridylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (20 mg, 0.038 mmol) and chromatography (silica gel, dichloromethane/methanol 4/1) gives the desired product in 79% yield (14 mg).
Reaction SMILES: [H][H].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[C:6]1[N:11]=[C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]2=[N:8][CH:7]=1)=[O:13].[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>[Pd]=O>[S:20](=[O:22])(=[O:21])([OH:24])[OH:23].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[CH:6]1[NH:11][C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]=2[NH:8][CH2:7]1)=[O:13]
Reactant: [H][H]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Agent: O=[Pd]
Agent: O=S(=O)(O)O
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1

Procedure:
Ten milligrams of palladium oxide was dispersed into 10 ml of 5% aqueous sulfuric acid solution, and then the catalyst was activated with hydrogen gas. Then, 10 ml of 5% aqueous sulfuric acid solution containing 50 mg of biopterin was added to the above dispersion. After the catalytic reduction was conducted by agitating the resulting mixture for 3 hours under normal temperature and normal pressure in a hydrogen atmosphere, the catalyst was filtered off from the reaction mixture to give a sulfuric acid solution of tetrahydrobiopterin having a (6R)/(6S) ratio of 70/30 as measured by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6](N)[C:7]=1[Cl:8].C(N=C=S)(C)C.[CH:17]1([N:23]=[C:24]=[N:25]C2CCCCC2)[CH2:22]CCC[CH2:18]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:10][C:24]([NH:23][CH:17]([CH3:22])[CH3:18])=[N:25][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)N=C=S
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
5,6-Dichloro-1,2-phenylenediamine (0.61 g, 3.4 mmol), and isopropyl isothiocyanate (0.39 g, 3.8 mmol) were combined in anhydrous pyridine (10 mL) and were heated to 80° C. for 15 min. Dicyclohexylcarbodiimide (1.06 g, 5.14 mmol) was then added and the resulting mixture was allowed to stir at 100° C. for 5 h. Toluene (30 mL) was added and the mixture was concentrated by rotary evaporation leaving a brown residue. The product was further purified by silica gel chromatography using 6.5:3:0.5 ethyl acetate/hexane/triethylamine to afford a gummy solid which was recrystallised from acetonitrile to give 0.46 g (60%) of a tan solid; m.p. 218-220° C.