Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>O>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:3])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Yield: 30.2 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.0 g of thiourea, 4.0 g of 1-[4-(4-chlorophenyl)butyl]-4-(3-chloropropyl)piperazine dihydrochloride and 50 ml of reagent ethanol. The hydrolysis was effected with 4.0 g of sodium hydroxide in 50 ml of water. Work-up of the free base, as described above followed by purification on a silica gel column (methylene chloride:methanol, 97:3), precipitation as the hydrochloride salt and recrystallization from reagent ethanol, gave 0.6 g (16% of theory) of 3-{4-[4-(4-chlorophenyl)butyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 254°-259° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cccs1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cccs1

Procedure:
70 mg (0.271 mmol) of 2-amino-6-sulfanyl-4-thiophen-2-ylpyridine-3,5-dicarbonitrile, together with 79 mg (0.325 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 91 mg (1.084 mmol) of sodium bicarbonate, were stirred in 2 ml DMF at room temperature overnight. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Chromasil, water/acetonitrile—without acid). This gave 94 mg (71% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[C:5]([Cl:14])=[CH:4][N:3]=1.COC1C=CC(C[NH2:22])=CC=1.FC(F)(F)C(O)=O>CN(C=O)C>[Cl:14][C:5]1[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])=[N:7][C:2]([NH2:22])=[N:3][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC[C@H](C)Oc1nc(Cl)ncc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1nc(N)ncc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2,5-dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine (intermediate 91, 1.26 g, 4.15 mmol) and 4-methoxybenzylamine (0.65 ml, 4.97 mmol) in DMF (7 ml) was heated at 50° C. for 18 h. The reaction mixture was partitioned between aqueous 1M HCl and DCM, extracted with DCM (2×), the combined DCM layers were washed with water, dried over Na2SO4 and evaporated. To the residue was added trifluoroacetic acid (3.93 ml, 51.0 mmol) and the reaction mixture stood at room temperature for 18 h, heated for 5 h at 70° C., stood 3 days at room temperature, heated at 80° C. for 2 days. The reaction mixture was evaporated and purified by a combination of normal and reversed phase chromatography (RP 3) to give the title compound as a colorless oil. (UPLC-MS 7) tR 0.74; ESI-MS 218.1 and 220.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1
Reactant: NC1CCCC1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)nc(NC2CCCC2)c1[N+](=O)[O-]
Yield: 84.8 %

Procedure:
Cyclopentylamine (5.2 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine (10.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (11.2 g) in a yield of 84.8%. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 2H), 4.41 (m, 1H), 2.64 (s, 3H), 2.01-2.15 (m, 2H), 1.61-1.76 (m, 4H), 1.45-1.63 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:17]=1
Reactant: Oc1ccccc1Cl
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccnc(Oc2ccccc2Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chlorophenol (10.5 g) in 150 mL dry THF) at 0° C. under argon was added 88 mL of a 1.0 M solution of potassium t-butoxide in THF. The reaction mixture was stirred for 15 minutes and then cooled to −78° C. A solution of 4-Chloro-2-methanesulfonyl-pyrimidine (14.2 g, 2.6 mmol) in 160 mL of dry THF was slowly added over 25 minutes. The reaction mixture was stirred for an additional 30 minutes at −78° C., and then quenched by addition of 60 mL saturated aqueous ammonium chloride, and evaporated under reduced pressure to remove THF. 200 mL water, and 200 mL EtOAc were added, the organic phase was collected, and the aqueous phase was washed twice with 150 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 10% EtOAc/Hexanes) to 10.2 g of 4-Chloro-2-(2-chloro-phenoxy)-pyrimidine. Mass Spec. M+H=242.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([S:26][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41].Cl[CH2:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50].C(OCC)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[C:24]([S:26][CH2:48][C:49](=[O:50])[N:51]([CH3:53])[CH3:52])[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:41])([F:42])[F:43]
Reactant: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tetrabutylammonium fluoride (1.1 ml of a 1M solution in THF) was added to (R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 28) (0.50 g) in anhydrous THF (5 ml) at −70° C. After 15 minutes 2-chlorodimethylacetamide (0.17 ml) was added and the mixture was allowed to warm up then was stirred at ambient temperature for 45 minutes. Ethyl acetate (80 ml) was added and the mixture was washed with brine (100 ml) then dried and volatile material was removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 10-50% ethyl acetate/hexane to give the title compound (0.30 g) as a solid. NMR (CDCl3) 1.72 (s, 3H), 2.97 (s, 3H), 3.08 (s, 3H), 3.71 (s, 2H), 4.76 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d, 1H), 8.32 (d, 1H), 9.05 (s, 1H); MS (ESP−): 383.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:32])[O:17][C@H:16]([CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH2:30]O)[CH:24]=[CH:23]3)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH2:18][C@@H:16]4[CH2:15][O:14][C:13]([CH3:32])([CH3:12])[O:17]4)[CH:21]=3)[CH:26]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC1(C)OC[C@@H](COc2ccc3cc(CO)ccc3c2)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCc2ccc3cc(OC[C@@H]4COC(C)(C)O4)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.5 g, 3.28 mmol), [6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-yl]-methanol (0.9 g, 3.12 mmol) and triphenylphosphine (0.83 g, 3.16 mmol) in DCM (20 ml) is cooled to 0° C. Diethyl azodicarboxylate (0.5 ml, 3.17 mmol) is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/iso-hexane) to obtain white solid. The product obtained is once again purified by column chromatography (neutral alumina, EtOAc/petroleum ether) to obtain 4-[6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid methyl ester as white solid; 1H NMR (d6-DMSO): 1.32 (3H, s), 1.38 (3H, s), 3.77-3.82 (4H, m), 4.08-4.16 (3H, m), 4.46-4.49 (1H, m), 5.30 (2H, s), 7.15-7.21 (3H, m), 7.37 (1H, d, J=2.0 Hz), 7.53 (1H, dd, J=8.50, 1.5 Hz), 7.83 (2H, dd, J=9.0, 6.0 Hz), 7.92 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].CCOCC>C(O)C>[NH2:23][C:21]1[S:22][CH:13]=[C:12]([C:11]2[CH:16]=[CH:17][C:8]([O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Solvent: CCOCC
Solvent: CCO
Product: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1

Procedure:
A 8.0 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride and 2.3 g of thiourea were stirred in 70 ml of ethanol under reflux for 1 hour. After cooling, 100 ml of ether was added, and the precipitating crystals were recovered by filtration, resulting in 7.8 g (82.1%) of hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy) phenyl]thiazole. Recrystallized from 80% ethanol m.p., 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:5]
Reactant: C/C=C/c1ccc(C(=O)N(CC)CC)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(C(=O)N(CC)CC)c(Cl)c1
Reaction time: 24 h
Yield: 67 %

Procedure:
To the crude (E)-2-chloro-N,N-diethyl-4-(prop-1-enyl)benzamide in 100 mL of absolute ethanol was added 10% Pd/C catalyst (1 g). The mixture was stirred under 1 atm of hydrogen, maintained by a balloon, for 18 h. Starting material still remained and so additional 10% Pd/C (0.5 g) was added and the reaction was charged with a fresh hydrogen balloon and stirred and additional 24 h. The reaction mixture was filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 8:1 to 6:1 hexane/EtOAc) to afford 2.15 g (67%) of the title compound. 1H NMR (CDCl3): δ 7.12 (d, 1H, J=1.1 Hz), 7.09 (d, 1H, J=7.7 Hz), 7.02 (dd, 1H, J=1.6, 7.7 Hz), 3.75-3.68 (m, 1H), 3.32-3.25 (m, 1H), 3.11-3.06 (m, 2H), 2.50 (t, 2H, J=7.7 Hz), 1.60-1.52 (m, 2H), 1.19 (t, 3H, J=7.1 Hz), 0.99 (t, 3H, J=7.1 Hz), 0.87 (t, 3H, J=7.4 Hz). LRMS (ESI): 254.10/256.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 3,4-dichlorobenzaldehyde and acetophenone, 3-(3,4-dichlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].C1COCC1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>CCCCCC>[F:22][C:23]1[CH:24]=[C:25]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CCCc1ccc(Br)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 60 °C
Yield: 99.6 %

Procedure:
In a nitrogen atmosphere, a solution prepared by mixing 90.33 g of 4-propylbromobenzene, 2.62 g of tetrakis-triphenylphosphine palladium, 240 mL of an aqueous potassium carbonate solution (2 mol/L), and 450 mL of THF was heated to 60° C., and 71.65 g of 3,5-difluorophenylboronic acid was added to the solution over 30 minutes. The resultant mixture was stirred at 60° C. for 30 minutes and then allowed to cool. Then, hexane was added to the mixture to separate an organic layer, and the organic layer was washed with saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to yield 104.92 g of 3,5-difluoro-1-(4-propylphenyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.2 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 12 mL methylene chloride is added 1.14 g triphenylphosphine followed by 0.336 g 3-hydroxypyridine. After stirring for 5 minutes, 0.55 mL diethyl azodicarboxylate is added slowly. After 1 hour, solvent is evaporated and the residue subjected to flash chromatography to obtain methyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoate, m.p. 57-58°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:13][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C:4]([C@@H:3]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:5][C:6]=2[CH:12]=1
Reactant: Cc1cc(C(=O)N[C@@H](CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90 mg (0.2 mmol) of N-[(1S)-2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is placed in 2 mL of dichloromethane, combined with 0.03 g (0.25 mmol) of triethylamine and while being cooled in the ice bath combined with 0.03 g (0.23 mmol) of methanesulfonic acid chloride. Then the mixture is heated to ambient temperature and stirred for 24 hours. Then the solvent is eliminated in vacuo and the residue purified by chromatography on silica gel (gradient: dichloromethane/methanol=100:5). Yield: 27 mg (25%); Rf value: 0.20 (silica gel; dichloromethane/methanol=95:5); C23H26ClN5O4S (504.01); mass spectrum: (M+H)+=504/506 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:23][CH3:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH:36][CH2:37][C:38]#[CH:39]>>[CH2:23]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:39]#[C:38][CH2:37][NH:36][CH3:35])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH2:25][CH2:26][OH:27])[CH3:24]
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Reactant: C#CCNC
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C#CCNC)cc3)nsc2c1

Procedure:
In analogy to example 36.1, {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine and N-Methylpropargylamine were converted to yield 2-[Ethyl-(4-{3-[4-(3-methylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanol as brown oil, MS: 438 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]=[N+]=[N-])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][NH2:35])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN=[N+]=[N-])c3)c2)Cc2ccccc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
The compound of step 1 (0.185 g, 0.360 mmol) and triphenylphosphine (0.149 g, 0.539 mmol) were dissolved in a mixture of 3 ml of THF and 3 ml of water, and the solution was stirred overnight at room temperature. The mixture was evaporated to dryness and purified by silica gel chromatography (DCM/methanol/28% ammonia gradient, 70:30:0 to 0:100:0 to 0:90:10) to yield 0.17 g of the title compound.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(O)(=[O:18])C1C=CC=NC=1.[Na].C(O)(=O)C1C=CC=NC=1>>[OH:18][C:4]1[N:3]=[CH:2][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: [Na]
Product: O=C(O)c1cccnc1O
Reaction time: 120 h
Yield: 72.5 %

Procedure:
The microorganisms with the designation Ki101 (DSM 6920) were incubated in 800 ml of mineral salt medium (Table 1 below) with addition of 8 mmol of 6-methylnicotinic acid in a 1 l Fernbach flask at 30° C. on a shaker at 100 rpm. The inoculum was 5 percent (v/v). After 5 days, the OD650 was about 0.5. Then the cells were harvested and washed once with 50 m molar phosphate buffer, pH 7.0. Then the cells were resuspended in 20 ml of 50 mM of phosphate buffer, pH 7.0 containing 200 mg (1.38 mmol) of nicotinic acid-sodium salt. The OD650 was 20. After 6 hours incubation on a shaker at 30° C., no more nicotinic acid could be detected by thin-layer chromatography. Then the biomass was centrifuged off and the supernatant acidified to pH 2.5 to precipitate the 2-hydroxynicotinic acid. No contamination in the isolated product could be detected by 1H-NMR (DMSO) analysis. Altogether 140 mg (1 mmol) of 2-hydroxynicotinic acid corresponding to a yield of 72 percent relative to nicotinic acid could be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:33])(=[O:32])[NH2:34])=[O:14])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.5 mmol) of 3-(4-methoxybenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.93 g (17.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 1.5 g (yield: 31.0%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[C:22]([F:31])[CH:21]=1>C(O)(C)C>[Cl:8][C:6]1[N:7]=[C:2]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:29]=[CH:30][C:20]([Cl:19])=[CH:21][C:22]=3[F:31])[CH2:26]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)nc(N2CC(Oc3ccc(Cl)cc3F)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 4.87 mmol) in isopropanol (15 mL) was added DIPEA (1.3 mL) and 3-(4-chloro-2-fluorophenoxy)azetidine (0.600 g, 2.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g) as a solid. Observed mass (M+1): 329. The crude material was taken to next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=3)[N:8]=2)[CH2:23]1
Reactant: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](N)C3)ccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-6-(4-(diethylamino)phenylamino) pyridin-2-yl)piperidin-3-ylcarbamate (1.41 g, 2.92 mmol) in CH2Cl2 (2 mL) was treated with TFA (4 ml) and stirred at rt for 4 h. The reaction mixture was concentrated and the residue dissolved in CH2Cl2 and washed with 1N NaOH and concentrated to give 1.07 g of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(diethylamino)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=383.25.