Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=O)[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:26])[CH:17]=1)([OH:15])[C:11]([F:14])([F:12])[F:13]
Reactant: C1COCCN1
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)O)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)N2CCOCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid (180 mg) and morpholin (0.04 mL) in DMF (6 mL), were treated with 4-methyl-morpholine (0.140 mL) and HBTU (241 mg). The reaction mixture was stirred at r.t. for 17 h. The reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 70:30) to give the title compound as white solid (134 mg). MS (m/e)=492.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 196 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(3-chlorophenyl)-2-oxoazepan-3-ylcarbamate (35 mg, 0.10 mmol) in DCM (2 mL) was added 4.0 M HCl in dioxane (0.258 mL, 1.03 mmol) at rt under argon. The reaction was stirred at rt for 6 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-amino-1-(3-chlorophenyl)azepan-2-one hydrochloride (27 mg, 0.098 mmol, 95% yield) as white solid. Anal. Calcd. for C12H15ClN2O m/z 238.2. found: 239.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:16][C:17]#[N:18])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(F)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cncc(F)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 43 %

Procedure:
To a mixture of 5-fluoropyridin-3-ol (0.95 g, 8.40 mmol) and K2CO3 (1.16 g, 8.40 mmol) in CH3CN (6 mL) was added dropwise 2-bromoacetonitrile (1.01 g, 8.42 mmol) at rt and upon the end of addition the mixture was stirred at rt for 40 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a yellow solid (0.55 g, 43%).
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH3:11][S:12](Cl)(=[O:14])=[O:13].Cl>C(N(CC)CC)C>[CH3:11][S:12]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)NCC(C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
29.4 g of ethyl 2-hydroxypropylcarbamate are dissolved in 27 g of triethylamine and 22.9 g of methanesulphonyl chloride are added dropwise thereto at 15°-20° C. over 1 hour while stirring. The thickening reaction mixture is stirred for 2.5 hours and then poured into ice-water. The mixture is acidified by means of 2 N hydrochloric acid and extracted three times with methylene chloride. The extracts are washed neutral with water and dried over sodium sulfate. After evaporating the solvent, there is obtained ethyl 2-(methylsulphonyloxy)propylcarbamate (nD20 =1.4577) which can be used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 409.09 g/mol.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)[CH:16]=[O:17]
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to those described for D4 starting from 6-(trifluoromethyl)3-pyridinol and 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: C[CH:2](C)[C@@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]1=[O:36])[C:4]([OH:6])=[O:5].O=C1C2C(=CC(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)=CC=2)CN1[C@@H](C)C(OC)=O>>[O:36]=[C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=4)=[O:24])=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)[CH2:15][N:7]1[C@@H:3]([CH3:2])[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: C[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 82 %

Procedure:
The compound of example 367 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 366.
Reaction SMILES: [CH2:1]([N:3]([C:5]([NH:7][C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)=[O:6])[NH2:4])[CH3:2].[CH2:14]=O.[OH-].[K+]>CO>[CH2:1]([N:3]1[C:5](=[O:6])[N:7]([C:8]2[S:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH2:14][NH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCN(N)C(=O)Nc1nnc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN1NCN(c2nnc(C)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)[CH3:2].O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:3][C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC=C2OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazine hydrate 98% were added dropwise. The solution was stirred at room temperature for 5 hours, then heated at 60° C. for further 5 hours. The solvent was removed in vacuo and the residue taken up with diethyl ether and the resulting precipitate collected by filtration giving 0.8 g of the title compound, that was employed in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]([C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])([OH:14])[CH3:13])=[CH:3]1
Reactant: CC(=O)c1scnc1C
Reactant: Brc1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ncsc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromofuran (6.8 g) in diethylether (15 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 18.4 ml) in diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 1 hour, 5-acetyl-4-methylthiazole (5 g) in diethylether (15 ml) was added dropwise. After a further 3 hours at -70° C., the mixture was allowed to warm to room temperature and was then left overnight. The mixture was poured into water and extracted with diethylether. The product thus obtained was crystallised from diethylether, m.p. 102°-104° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C@H:4]([C@@H:6]([CH3:9])[O:7][CH3:8])[NH2:5].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[CH3:11][N:2]([CH3:1])[C:3](=[O:10])[C@H:4]([C@@H:6]([CH3:9])[O:7][CH3:8])[NH:5][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1
Reactant: CO[C@H](C)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CO[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of N,N,O-trimethyl-L-threoninamide (1198 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (996 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (680 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:14]([O:15][CH3:16])=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=2[O:17][CH3:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[S:20][N:21]=[C:22]2[CH:27]=[C:26]([CH:28]([CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[O:36])[C:29]([O:31]CC)=[O:30])[CH:25]=[CH:24][C:23]=12.N1SN=C2C=C(CC(OCC)=O)C=CC=12.C(=O)([O-])[O-].[K+].[K+].NC1C=C(CC(OCC)=O)C=CC=1N.S(=NC1C=CC=CC=1)=O.[Na]>CC(C)=O.C1(C)C=CC=CC=1.C(O)C.C(O)(=O)C>[N:19]1[S:20][N:21]=[C:22]2[CH:27]=[C:26]([C:28]3[C:29](=[O:30])[O:31][C:35]([OH:36])([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[C:34]=3[CH2:11][C:10]3[CH:13]=[C:14]([O:15][CH3:16])[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:8]([O:17][CH3:18])[CH:9]=3)[CH:25]=[CH:24][C:23]=12
Reactant: COc1cc(C=O)cc(OC)c1OC1CCCC1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)c1ccc2nsnc2c1
Agent: CCOC(=O)Cc1ccc(N)c(N)c1
Agent: CCOC(=O)Cc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(C2(O)OC(=O)C(c3ccc4nsnc4c3)=C2Cc2cc(OC)c(OC3CCCC3)c(OC)c2)cc1

Procedure:
0.368 g of 4-cyclopentyloxy-3,5-dimethoxybenzaldehyde (“A”) and 0.52 g of ethyl 2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxobutanoate, m.p. 89° (obtainable by reaction of 5.5 g of ethyl 2-(2,1,3-benzothiadiazol-5-yl)acetate with 5.5 g of 2′-bromo-4-methoxyacetophenone and 4 g of potassium carbonate in 200 ml of acetone, 18 hours under reflux; ethyl 2-(2,1,3-benzothiadiazol-5-yl)acetate, m.p. 40-41° is obtained by reaction of 24.3 g of ethyl 3,4-diaminophenylacetate and 26.9 ml of thionylaniline in 80 ml of toluene, 4 hours under reflux) are added to a solution of 34 mg of sodium in 10 ml of ethanol and the mixture is heated under reflux for one hour. After addition of 1.4 ml of acetic acid, it is heated for a further 16 hours. The solvent is removed and the residue is worked up in the customary manner. 3-(2,1,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one is obtained, FAB 575.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NCc2ccccc2)nc1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and 10% Pd/C (202 mg) in ethanol (20 mL) was placed in a Paar bottle and shaken under hydrogen (50 PSI) for 3 h. The mixture was filtered through Celite using dichloromethane and concentrated in vacuo to afford 1.76 g of 2-benzylamino-5-aminopyridine as a burgundy oil.
Reaction SMILES: [OH:1][C:2]1([CH2:15][SH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24](=[O:30])[CH:23]=[CH:22]2>C(#N)C>[OH:1][C:2]1([CH2:15][S:16][C:22]2[C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH3:17])[CH:20]=3)[C:25](=[O:29])[C:24](=[O:30])[CH:23]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Reactant: COc1ccc2c(c1)C=CC(=O)C2=O
Solvent: CC#N
Product: COc1ccc2c(c1)C(SCC1(O)CCN(C(=O)OC(C)(C)C)CC1)=CC(=O)C2=O

Procedure:
tert-butyl 4-hydroxy-4-{[(7-methoxy-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}piperidine-1-carboxylate was synthesized using tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate, 6-methoxynaphthalene-1,2-dione, acetonitrile as the solvent and conditions outlined in procedure F [step (i)]. The crude intermediate was used in step (ii) without any further purification.
Reaction SMILES: [S:1](=[O:24])(=[O:23])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([OH:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].S(Cl)(=O)(=O)N>>[S:1](=[O:23])(=[O:24])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: NS(=O)(=O)Cl
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
Sulfamoylation is the key step in the synthesis of 17β-Hydroxyestra-1,3,5(10)-trien-3-yl sulfamate, a potent estrogen after oral administration. 17-Oxo-1,3,5(10)-triene-3-ol (estrone) is reacted with sulfamoyl chloride to yield 17-Oxoestra-1,3,5(10)-trien-3-yl sulfamate, which is in turn converted to 17β-Hydroxyestra-1,3,5(10)-trien-3-yl sulfamate by means of a complex hydride reagent. According to this invention, the preferred complex hydride reagent is sodium borohydride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2cccc(F)c2)n1
Product: Cc1cc(Cl)nc(/C=C/c2cccc(F)c2)n1
Yield: 82.7 %

Procedure:
In analogy to example 12c), by heating (E)-6-methyl-2-[2-(3-fluoro-phenyl)-vinyl]-pyrimidin-4-ol 1 (1.12 g, 4.86 mmol) in POCl3 (9 ml, 0.1 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-6-methyl-2-[2-(3-fluoro-phenyl)-vinyl]-pyrimidine (1 g, 86%) as a white solid. EI mass spectrum, m/e: 248 (M calculated for C14H13ClFN2: 248).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCC1CC1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.8 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water, 15 ml of ethanol and 2 ml of 4 N aqueous lithium hydroxide, 2.2 g of cyclopropylmethyl bromide are added while stirring and the pH of the mixture adjusted with lithium hydroxide to 7.0 during 24 hours. Thereupon,it is filtered, the filtrate diluted with water, washed with diethyl ether and acidified with concentrated hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid melting at 200°-204°.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)(C)[CH2:8][OH:9])(=[O:4])=[O:3].C1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.Cl.NC(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][CH:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)CO
Agent: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Product: CS(=O)(=O)OCC(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-6-carbaldehyde (1A) and 2-amino-1,3-propanediol hydrochloride (Simga) gave 2-((6-chrysenylmethyl)amino)-1,3-propanediol methanesulfonate mp 208°-209°, (CH3OH/Et2O), (C,H,N,S).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].BrCC(OC(C)(C)C)=O.C([O-])(=O)CC.C([O:27][C:28](=[O:44])[CH2:29][N:30]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])(C)(C)C>CC(N(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:43][C:39]1[CH:38]=[C:37]([N:30]([CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:29][C:28]([OH:44])=[O:27])[CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C(C)N(CC(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)CBr
Agent: CCC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)N(CC(=O)O)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
A sealed tube containing a suspension of Intermediate 39A (0.500 g, 2.340 mmol), potassium carbonate (0.485 g, 3.51 mmol), potassium iodide (0.039 g, 0.234 mmol), and tert-butyl bromoacetate (0.415 ml, 2.81 mmol) in DMA (4.68 mL) was warmed to 100° C. After 3 h, additional tert-butyl bromoacetate (0.415 mL, 2.81 mmol) was added and the reaction was heated at 100° C. After 22 h, the reaction was stopped and cooled to rt. The reaction was filtered, eluting with diethyl ether. The filtrate was partitioned between diethyl ether and water and the layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give a clear, yellow liquid weighing 1.35 g. Purification by normal phase chromatography gave 1.2:1 mixture of Intermediate 39A and methyl 2-(2-(tert-butoxy)-2-oxoethyl)(3-chlorophenyl)amino)propanoate (0.375 g) as a clear, colorless viscous oil. MS (ESI) m/z: 350.0 (M+Na)+. A clear, colorless solution of Intermediate 39A and methyl 2-((2-(tert-butoxy)-2-oxoethyl)(3-chlorophenyl)amino)propanoate (0.375 g, 1.144 mmol) in 50% TFA/DCM (16.34 mL) was stirred at rt. After 3 h, the reaction was concentrated to give a pink oil. The oil was partitioned between EtOAc and 0.5 M NaOH and the layers were separated. The organic layer was extracted with 0.5 M NaOH (2×). The combined aqueous layers were extracted with EtOAc, acidified with 1.0 N HCl to give a cloudy mixture, and then extracted with EtOAc (3×). The organic layers following acidification were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired product (0.130 g) as a clear, yellow residue. MS (ESI) m/z: 272.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([Mg]Cl)[CH:13]=[CH2:14]>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH:13]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Cl
Reactant: O=CCOCc1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)COCc1ccccc1
Temperature: 0 °C

Procedure:
2-(Benzyloxy)acetaldehyde (5 g, 33.3 mmol) in dry THF (10 mL) was added dropwise to a stirred and cooled solution of allylmagnesium chloride (25 mL, 2 M in THF, 50 mmol) in THF (100 mL) at −78° C. After the addition, the solution was allowed to warm to 0° C. and quenched with saturated NH4Cl solution. After standard aqueous work up, the residue was purified over silica using EtOAc and hexane to give 1-(benzyloxy)pent-4-en-2-ol (11).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[N:23]=[C:24]([C:28](=O)[CH3:29])[S:25][C:26]=1[CH3:27].C([BH3-])#N>[Zn]>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:28]([C:24]3[S:25][C:26]([CH3:27])=[C:22]([CH3:21])[N:23]=3)[CH3:29])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC(=O)c1nc(C)c(C)s1
Agent: [BH3-]C#N
Agent: [Zn]
Product: Cc1nc(C(C)Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)sc1C

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-(4,5-dimethyl-thiazol-2-yl)-ethanone with zinc-modified cyanoborohydride yielded a mixture of epimers of the title compound as a colorless solid. MS (ESI): m/z=418.4 [M+H]+.
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1.CO>[OH:25][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
At 0° C., sodium tetraborohydride (78 mg, 2 mmol) was added to a solution of ethyl (1-methyl-2-phenyl-1H-indol-3-yl)-oxo-acetate (8a) (630 mg, 2.05 mmol) in a mixture of tetrahydrofuran (10 mL) and methanol (15 mL). The mixture was stirred at room temperature for 2 hours and then hydrolyzed with water. Methanol and tetrahydrofuran were removed under reduced pressure and the residue was diluted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane) to afford the desired alcohol (8b) (440 mg, 1.42 mmol, 69%).