Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](=O)([OH:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH2:1]([S:8][CH:9]([CH:12]([O:13][CH3:14])[O:15][CH3:16])[CH2:10][NH:11][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)O
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(OC)C(CNC(=O)OC(C)(C)C)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2-(Benzylthio)-3,3-dimethoxypropan-1-amine (1 g) was dissolved in tetrahydrofuran (7 mL), and 1N aqueous sodium hydroxide solution (10 mL) was added. A solution of t-butyl bicarbonate (993 mg) in tetrahydrofuran (3 mL) was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over sodium sulfate. The obtained solution was filtrated through basic silica gel, and concentrated to give the title compound (1.39 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:4]([F:16])[CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:15]/[C:19](/[CH3:21])=[CH:18]\[C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([F:16])[CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)Oc1cc(NC(N)=O)c(F)cc1Cl
Product: CCOC(=O)/C=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
from 4-chloro-2-fluoro-5-isopropoxyphenylurea and ethyl acetoacetate using finely powdered Amberlyst®-15 (an organic, polymeric resin having free sulphonyl groups) as the catalyst there is obtained ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]crotonate, m.p. 142°-144° C. and from this intermediate in dimethylformamide with sodium hydride there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 228°-230° C.;
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH:33]([C:36]1[NH:37][CH2:38][CH2:39][CH:40]=1)([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>C(Cl)CCl>[CH:33]([CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:20])([CH3:21])[CH3:1])=[N:6]1)([CH3:35])[CH3:34]
Reactant: CC(C)C1=CCCN1
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N3CCCC3C(C)C)c2c1
Temperature: 45 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid 1 mL DMF was added 23.0 mg HOBt, 22.5 mg 2-isopropylpyrroline hydrochloride, 38.3 mg EDC, and 64.6 mg DIEA in that order. The mixture was stirred heated at 45° C. for two hours and purified by RP-HPLC using 60-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.05 min. (m/Z=386.4, 408.3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 22 g (100 mmol) 4-iodophenol, 17 g (100 mmol) 1-(2-chloro-ethyl)-pyrrolidine (used as the hydrochloride) and 55.3 g (400 mmol) K2CO3 in 400 mL DMF is stirred for 48 h at RT. The solvent is evaporated down i.vac., the residue is combined with water, the aqueous phase exhaustively extracted with EtOAc, the combined organic phases are washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 85:15:1.5).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10](OC)=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.O.[NH2:26][NH2:27]>CCO>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:26][NH2:27])=[O:11])=[C:7]([C:14]([NH:15][CH3:16])=[O:17])[C:6]=2[CH:18]=1
Reactant: NN
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Solvent: CCO
Solvent: O
Product: CNC(=O)c1c(C(=O)NN)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Yield: 100 %

Procedure:
To a suspension of compound methyl 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate in EtOH was added hydrazine hydrate (421 mg, 7.16 mmol). The mixture was refluxed overnight. Then it was concentrated in vacuo and the resulting solid was washed with MeCN to give the compound 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, yield: 100%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 10.33 (br s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 5.03 (br s, 3H), 3.22 (s, 3H), 3.20 (s, 3H), 2.87 (d, J=4.8 Hz, 3H). MS (M+H)+: 419/421.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2OC(C)(C)O[C:33](=[O:39])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[CH2:32][C:33](=[O:39])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 6-(3-chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (155 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14]C3C=CC=CC=3)[CH2:10][CH:9]2[C:21]([O:23]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[C:27]1([CH2:26][C:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:9]2[CH2:10][N:11]([CH2:14][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:13][N:8]2[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[OH:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)(Cc1ccccc1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Ethyl 1,4-bis(phenylmethyl)-2-piperazine carboxylate (8.2 g, 24 mmol) was dissolved in tetrahydrofuran (100 mL) under argon atmosphere. With ice cooling, a 1.0 M solution of benzyl magnesium bromide in tetrahydrofuran (100 mL, 0.10 mol) was added dropwise thereto over 30 minutes. After stirring at room temperature for 14 hours, an aqueous saturated ammonium chloride solution (300 mL) was added dropwise thereto with ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane to hexane:ethyl acetate=5:1) to obtain the title compound (5.1 g, yield 44%).
Reaction SMILES: Br[CH:2]1[CH:10]([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[C:3]1=[O:13].[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:13])[N:22]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:21][CH:2]3[CH:10]([OH:11])[C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2C(O)C1Br
Reactant: NC(=S)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OC1c2cc(Cl)ccc2C2(O)N=C(c3ccccc3)SC12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.6 g (2.3 mmol) of 2-bromo-5-chloro-3-hydroxyindan-1-one and 0.473 g (3.45 mmol) of thiobenzamide were dissolved in 5 ml of isopropanol. 0.478 ml (3.45 mmol) of triethylamine was added, and the mixture was then stirred at room temperature for 12 h and subsequently at 50° C. for 8 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel by initially using n-heptane/ethyl acetate 3/1 and then toluene/acetone 5/1. This gave 6-chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol having a melting point of 151-153° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[O:13][CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)c(O)c(C#N)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (11.29 g) was dissolved in N,N-dimethylformamide (230 mL), and potassium carbonate (49.20 g) and dimethylsulfuric acid (17.0 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. After the reaction solution was filtered, water was added and the precipitated crystal was collected by filtration to obtain the title compound (8.99 g) as a pale yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH3:23])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Cn1ncc2c(CCl)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2cccc3c2cnn3C)c(C=O)c1
Yield: 64.8 %

Procedure:
A mixture of 2-hydroxy-5-methoxybenzaldehyde (170 mg, 1.12 mmol), 4-(chloromethyl)-1-methyl-1H-indazole (1.12 mmol), and K2CO3 (618 mg, 4.48 mmol) was reflux in CH3CN (20 mL) for 2 h. The mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and MeOH as eluent to give 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde (215 mg, 81% for three steps) as a white solid. 1H NMR (400 MHz; DMSO) δ=10.39 (s, 1H), 8.20 (d, 1H), 7.63 (d, 1H) 7.36-7.64 (m, 2H), 7.23-7.29 (m, 2H), 7.18 (d, 1H), 5.58 (s, 2H), 4.06 (s, 3H), 3.34 (s, 3H). LRMS (M+H+) m/z 297.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH2:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]1([CH2:26][C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCC1CN(CCCc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)NCC1CN(CCCc2ccc(Cl)c(Cl)c2)CCO1
Yield: 9.6 %

Procedure:
A mixture of Intermediate 7 (0.030 g) and phenylacetic acid (0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W microwave oven, at full power, for 4 min. The crude mixture was purified by chromatography on silica gel (Varian Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1 followed by 2:1) to give thetitle compound as a colourless gum (0.004 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([N:20]([CH3:21])[CH3:19])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CNC
Product: CN(C)C(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylamine following the procedure set out in Example 8D to give the title compound. LC/MS: (PS-A2) Rt 3.40 [M+H]+ 309.95.
Reaction SMILES: C1C2C(=CC=C(S(N(CC(O)=O)C3C=CC(C)=CC=3)(=O)=O)C=2)CCN1.C(NCC1C=CC=CN=1)C.[CH2:36]([N:38]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1)[C:39](=[O:64])[CH2:40][N:41]([S:49]([C:52]1[CH:61]=[C:60]2[C:55]([CH2:56][CH2:57][N:58](C=O)[CH2:59]2)=[CH:54][CH:53]=1)(=[O:51])=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=1)[CH3:37]>C(O)=O>[CH2:36]([N:38]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1)[C:39](=[O:64])[CH2:40][N:41]([S:49]([C:52]1[CH:61]=[C:60]2[C:55]([CH2:56][CH2:57][NH:58][CH2:59]2)=[CH:54][CH:53]=1)(=[O:51])=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=1)[CH3:37]
Reactant: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc2c(c1)CN(C=O)CC2
Agent: CCNCc1ccccn1
Agent: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc3c(c2)CNCC3)cc1
Solvent: O=CO
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc2c(c1)CNCC2

Procedure:
prepared by reaction of [(1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine; due to the presence of formic acid in the eluent of the HPLC chromatography the product contained considerable amounts of N-ethyl-2-[(2-formyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl-amino]-N-pyridin-2-ylmethyl-acetamide (LC-MS: rt=0.77 min, 507 (M+1, ES+))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-2-carboxy-4-hydroxypyrrolidine (103 g) and potassium carbonate (64.6 g) in dimethylformamide (500 ml) was added methyl iodide (33.2 ml) at 0° C., and the mixture was stirred for three hours. The reaction mixture was poured into a mixture of water (1 l) and ethyl acetate (1 l), and the organic layer was separated, washed in turn with water (500 ml) and brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (800 ml) eluting with a mixture of hexane and ethyl acetate (1:2, V/V) to give (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxycarbonylpyrrolidine (105.2 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Br:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To tert-butyl(2-bromo-3-chlorophenyl)carbamate (0.4 g) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at RT for 3 hours and then concentrated. Water (10 mL) was added to the residue, and the mixture was extracted with DCM (2×20 mL). The organic phase was separated, washed with aqueous saturated NaHCO3 and saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give the title compound as a solid (0.2 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.03-6.99 (1H, m), 6.85-6.83 (1H, d, J=8.0 Hz), 6.65-6.63 (1H, d, J=8.0 Hz), 4.25 (2H, s).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[N:6]=[CH:7][C:8]=1Cl.[Cl-].[NH4+].[CH3:14][OH:15]>>[Cl:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[N:6]=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: CO
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Product: COc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Sodium metal (613 mg, 26.7 at-g) were dissolved in 35 ml of methanol. To this solution were added 4.15 g (23.18 mmol) of 4,5-dichloro-2-methyl-2H-pyridazin-3-one in four portions over 5 min. After stirring the suspension for 4 h at room temperature, the solution was neutralized by addition of 1 ml sat. ammonium chloride solution and concentrated in vaccuo. The residue was taken up in 100 ml of ethyl acetate, washed twice with water, drie over magnesium sulfate and concentrated in vaccuo to yield 3.94 g (22.6 mmol, 97%) of the title compound as a crystalline white solid, MS: 175.2, 177.0 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:32][CH2:33][CH2:34][CH3:35])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:32]([C:8]1[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]([Cl:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(C(=O)O)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Reaction time: 20 h

Procedure:
To a solution of 2-butyl-5-chloro-1-{5-[2-(1H-tetrazol-5-yl)-phenyl]-indan -1-yl}-1H-imidazole-4-carboxylic acid ethyl ester (50 mg, 0.1 mmol)in ethanol (2 mL) was added 2N sodium hydroxide (NaOH) (0.5 mL). The reaction mixture was stirred for 20 hours, and then concentrated in vacuo. The residue was diluted with saturated aqueous NaCl (10 mL) and neutralized with concentrated acetic acid (HOAc). The aqueous solution was extracted with chloroform (CHCl3) (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in EtOAc (0.5 mL) and hexanes were added to precipitate the product. The solid was filtered and dried in vacuo. 1H NMR (250 MHz, d6 -DMSO): d 7.62 (m, 5 H), 7.08 (s, t), 6.85 (m, 2 H), 6.15 (m, 1 H), 3.1-2.0 (m), 165 (m, 2 H), 140 (m, 2 H), 0.95 (t, 3 H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:10]=2[N:11]=1)[CH3:4].CO.Cl.O1CCOCC1>C(Cl)Cl>[N:11]1[C:10]2[CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=[N:7][C:6]=1[NH:5][C@@H:3]([CH3:4])[CH2:2][OH:1]
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a solution of 136 (39.5 g, 128 mmol), DCM (100 mL) and MeOH (100 mL) was added 4N solution of HCl in dioxane (160 mL, 640 mmol) and stirred for 18 h. The reaction was concentrated to afford a red oil. The residue was taken up in DCM/7N methanolic NH3 (100 mL, 9:1) and the mixture was sonicated for 5 min. The inorganic salt precipitate was removed by filtration and washed with the same solvent. The filtrate was concentrated to afford a viscous red oil. The crude product was purified by SiO2 chromatography (Biotage 40 M) eluting with DCM/7N methanolic NH3 (7:1). The recovered light brown oil crystallized to form 21.2 g (95%) (S)-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (138) as a brown solid: MS m/z (APCI-pos) M+1=209.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>>[CH3:1][S:2]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[O:18]
Reactant: CSc1ccc(N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1ccc(N)cc1

Procedure:
Following a similar procedure to that described in reference example 1, but starting from 4-methylthioaniline and using 1 equivalent of m-chloroperbenzoic acid, the title compound of the example was obtained as a white solid (80% yield).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.N1C=CC=CC=1.[C:26]([NH:36][C@H:37]([C:41]([O:43][CH2:44][CH:45]([CH2:52][O:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:46][CH2:47][O:48][C:49](Cl)=[O:50])=[O:42])[CH:38]([CH3:40])[CH3:39])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C=O)C.ClCCl>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:49]([O:48][CH2:47][CH2:46][CH:45]([CH2:44][O:43][C:41](=[O:42])[C@H:37]([CH:38]([CH3:40])[CH3:39])[NH:36][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:52][O:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:50])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCOC(=O)Cl)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCOC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (269 mg, 1.0 mmole in absolute DMF were added pyridine (198 mg, 2.5 mmole) and a solution of 3-(N-CBZ-L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl chloride (750 mg, 1.1 mmole) in 5 ml dichloromethane. The mixture was stirred for three days at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 120 mg
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]#[C:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH3:18].[Li].N>>[CH2:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]#[C:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC#CCCCC
Reactant: OCCCCCCBr
Agent: N
Agent: [Li]
Product: CCCCC#CCCC#CCCCCCCO

Procedure:
The use of a protected derivative of 6-bromohexanol can be avoided thus an excess of lithium 1,5-decadiyne in liquid ammonia is used and allowed to react directly with 6-bromohexanol to give 7,11-hexadecadiynol (bp 136°-138°/1 torr, nD21 1.4818). Acetylation with acetic anhydride or acetic acid-acetyl chloride converts the alcohol to the acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 10 °C

Procedure:
A mixture of 14.7 g of 5-methoxy-1H-indole, 30.7 g of the monohydrate of 4-piperidone hydrochloride and 150 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 81/2 hours and was then cooled. 300 ml of water were added to the mixture which caused crystallization and the mixture was cooled to 10° C. and filtered. The recovered product was empasted 3 times with water, twice with ethanol and twice with ether. The product was dried at 20° C. under reduced pressure to obtain 18.25 g of 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in the form of a clear yellow powder melting at 183° C.