Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(Br)C=C>C1COCC1>[O:11]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:15][CH:14]=[CH2:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1C(=O)CCc2ccccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To a solution of 7.3 g (50 mmol) 2-tetralone in 75 mL THF in a 3-neck round-bottomed flask, equipped with a gas inlet and septum, was added 36.7 mL LDA (55 mmol, 1.5 M in cyclohexane) at −30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a 30-minute period and 5.6 mL (65 mmol) allyl bromide was added. TLC analysis was used to monitor the reaction. After stirring for 24 hours at room temperature, the reaction mixture was quenched with 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting with 1 L of hexane, followed by 5 L of 5% ethyl acetate/hexane, and collecting 40 mL fractions. Fractions 65-82 gave 3.1 g (33%) of pure 1,2,3,4-Tetrahydro-2-oxo-1-(2-propenyl)-naphthalene as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH2:29][CH2:28]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3n2)CC1
Temperature: 180 °C
Yield: 78.5 %

Procedure:
A 0.5 ml microwave vial was loaded with 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide (8 mg, 0.019 mmol), 1-Methylpiperazine (0.25 ml, 2.246 mmol) and NMP (0.25 ml), sealed and heated to 180° C. for 2 hours. Purification by prep HPLC, followed by filtration of the product containing fractions through gave a Waters MCX cartridge, washing with MeOH and elution with 2M NH3 in MeOH and drying gave 6.3 mg 2-(4-methylpiperazin-1-yl)-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamid. MS (ESI) m/e+=423, m/e−=421 consistent with [M+H]+ and [M−H]−. HPLC retention time 5.42 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.25 (d, 1H, J=8.3), 7.67 (b, 1H), 7.42 (s, 1H), 7.26 (dd, 1H, J=8.0, 1.2), 3.90-3.50 (m, 12H), 2.74-2.66 (m, 4H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][NH:6][CH2:5][C:4]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])=[N:10][C:3]1=2.C(O)(=O)C.[Na].[CH3:41][C:42]([CH3:44])=O>CN(C=O)C>[CH:42]([N:6]1[CH2:7][C:2]([CH3:35])([CH3:1])[C:3]2[N:10]=[C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)=[O:17])[NH:8][C:4]=2[CH2:5]1)([CH3:44])[CH3:41]
Reactant: CC(C)=O
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(C)C)CC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (0.12 g, 0.26 mmol) (intermediate prepared in the synthesis of compound 451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodium triacetoxyborohydide (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8 mmol) were mixed and stirred at room temperature for 2 hours. The reaction was carefully quenched with water (10 mL) and the mixture was extracted with ethyl acetate (60 mL) and the organics was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by preparative TLC (DCM/10% MeOH) followed by a second preparative TLC (ethyl acetate/5% MeOH) to obtain the title compound as a white powder (4.1 mg, 8.1%). m/z (ES+) 510 (M+H)+.
Reaction SMILES: Br.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[N:13]=2)(=[O:29])=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccc4ccccc4c3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10 g of 4-(2-naphthyl)-thiazol-2-ylamine hydrobromide with 8.5 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred for 18 hours with 40 ml of pyridine. The resulting, red colored suspension was poured into 400 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and (sic) concentrated. The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 11.1 g of 3,4-dimethoxy-N-(4-naphthalen-2-yl-thiazol-2-yl)-benzenesulfonamide separated upon neutralization with concentrated hydrochloric acid in the form of colorless crystals, which were recrystallized from ethanol/water.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)O2

Procedure:
0.16 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 1.5 ml of 99.5% ethanol and 0.2 ml of tetrahydrofuran. 265 mg of a 9.55% w/w aqueous solution of sodium hydroxide were added dropwise, under a nitrogen stream at 0°-4° C., to the resulting mixture. The mixture was then reacted for a further 20 hours at 0°-5° C., after which it was neutralized, whilst ice-cooling, by adding 0.68 g of a 10% w/w aqueous solution of hydrochloric acid. The solvent was then distilled off under reduced pressure. The separated light reddish oil was further extracted with chloroform, and the chloroform extract was washed with water and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the chloroform under reduced pressure was subjected to column chromatography through silica gel and the desired 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionic acid was obtained from the fractions eluted with a 20:1 by volume mixture of benzene and 99.5% ethanol. Rf value on thin layer chromatography: 0.6 (tailing) [silica gel; developing solvent; benzene:99.5% ethanol=4:1 by volume].
Reaction SMILES: [OH:1]/[CH:2]=[C:3](/[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)\[C:4](OC)=O.[NH2:18][C:19]([NH2:21])=[S:20]>CO>[N:9]1([CH2:8][C:3]2[C:2](=[O:1])[NH:18][C:19](=[S:20])[NH:21][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: NC(N)=S
Reactant: COC(=O)/C(=C\O)Cn1ccc2ccccc21
Solvent: CO
Product: O=c1[nH]c(=S)[nH]cc1Cn1ccc2ccccc21
Temperature: 50 °C
Yield: 70.5 %

Procedure:
To a solution of methyl (2Z)-3-hydroxy-2-(1H-indol-1-ylmethyl)-2-propenoate (1.138 g, 4.92 mmol) in MeOH (20 mL) was added thiourea (1.0 g, 13.14 mmol) in one portion. The mixture was heated at 50° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (0.93 g, 3.47 mmol, 70.5% yield). LCMS: rt=2.28 min, [M+H+]=258
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH3:22])=[O:7].N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH3:22])=[O:7])=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.14 g, 0.36 mmol) in dichloromethane (5 mL) was added pyridine (0.032 mL, 0.39 mmol) and 4-nitrophenyl chloroformate (0.079 g, 0.39 mmol). The reaction was stirred at ambient temperature for one hour and concentrated in vacuo to give the title compound (0.20 g).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>CN(C)C=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][CH2:37][CH2:36][N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:20])=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]1)=[O:9])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane (commercially available) in N,N-dimethylformamide, to give the desired product as a colorless oil (44%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]#[N:28]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[CH:24]=[N:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: N#Cc1[nH]cnc1N
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)ccc1C(F)(F)F
Yield: 47.2 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (224 mg, 0.75 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-1H-imidazole (81 mg, 0.75 mmol) according to general procedure B yielded the title compound as a yellow solid (131 mg, 47%). MS (ISP) 371.1 [(M+H)+]; mp 217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][S:26][C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][S:26][C:27]3[S:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[N:31]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: BrCCCSc1nc2ccccc2s1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(C(OC2CCN(CCCSc3nc4ccccc4s3)CC2)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.6 %

Procedure:
To a mixture of 0.76 g (2.51 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 0.73 g (2.53 mmol) of 2-(3-bromopropylthio)benzothiazole, were added 6 ml of acetone and 0.35 g (2.53 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 15 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using chloroform alone first, and then a mixture of chloroform and methanol in the volume ratio 30:1 as the eluent, and the desired fraction was concentrated to give 0.52 g (41%) of 2-[3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propylthio]benzothiazole as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 382 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2nc(-c3ccccc3)sc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2nc(-c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5,7-Dichloro-2-phenylthiazolo[5,4-d]pyrimidine 65 was suspended in methanol and treated with morpholine. The reaction mixture was stirred at room temperature for 4 h. Solid was filtered to yield pure 4-(5-chloro-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)morpholine 66 as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=4)[C:27](=[O:34])C4C=CC=CC=4)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH:45]([N:48]=C=O)([CH3:47])[CH3:46].C(Cl)Cl>CCOC(C)=O>[CH:45]([NH:48][C:27](=[O:34])[N:26]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:19]=1)[CH3:25])[C:35]1[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=1)([CH3:47])[CH3:46]
Reactant: CC(c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)N(C(=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)NC(=O)N(c1ccc(S(C)(=O)=O)cc1)C(C)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 41 but using (1-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-(4-methylsulfanyl-phenyl)-amine (EXAMPLE 44, step 1) and iso-propyl isocyanate as the starting materials. Flash chromatography (CH2Cl2:EtOAc; 4:1) afforded the title compound as a foam.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:31]([CH2:30][CH2:29][O:28][CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: COCCC(=O)O
Product: COCCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-methoxypropanoic acid, the title compound was obtained in 80% purity by HPLC. MS(ESI+): m/z=421.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]([CH3:29])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:30])[C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][NH2:18])[N:14]=1)([CH3:29])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Yield: 91.2 %

Procedure:
2-Methyl-2-{[4-(3-phthalimidopropyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (31.1 g) obtained in Example 32 was dissolved in ethanol (400 mL), hydrazine monohydrate (10 mL) was added, and the mixture was refluxed for 2 hr. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water and dichloromethane were added to the residue, and the organic layer was washed with water, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give the title compound (20.1 g). The obtained compound was used in the next reaction without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:10][C:9]2([CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)[O:8][C:7]1=[O:18].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:19][C:5]1[S:1][C:2]([N:6]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:7]2=[O:18])=[N:3][CH:4]=1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A solution containing 3′-(thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (2.80 g, 10.55 mmol) and N-bromosuccinimide (3.90 g, 21.86 mmole) in N,N-dimethylformamide (15 mL) were stirred at RT overnight. The mixture was diluted with chloroform, washed with saturated aqueous potassium carbonate and then with brine, dried through magnesium sulfate, and then the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a pale solid (1.70 g), m/z 343, 345 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:29])(=[O:28])[N:11]=[C:12]1[NH:16][C:15](=[O:17])[C:14](=[CH:18][C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[S:13]1)=[O:4].O[Li].O>C1COCC1.O>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([CH:18]=[C:14]3[S:13][C:12](=[N:11][S:10]([C:9]4[CH:8]=[CH:7][S:6][C:5]=4[C:3]([OH:4])=[O:2])(=[O:28])=[O:29])[NH:16][C:15]3=[O:17])=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C1NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(=NS(=O)(=O)c2ccsc2C(=O)O)SC1=Cc1ccc2c(c1)OCO2

Procedure:
35 mg (0.08 mmol) of 3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-thiazolidin-2-ylidenesulfamoyl)-thiophene-2-carboxylic acid methyl ester (Example 5) were dissolved in THF/water. 6 mg of LiOH.H2O were added, and the reaction was followed by TLC. After complete saponification the reaction medium was acidified to pH 3.5, where upon the desired compound precipitated. Washing and drying afforded 25 mg (70%) of 3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-thiazolidin-2-ylidenesulfamoyl)-thiophene-2-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:15])[N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Cl:16][C:17]([SH:20])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:16][C:17]1[S:20][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[N:15]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1CCN(C(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of ethyl 1-[amino(imino)methyl]piperidine-4-carboxylate hydrochloride (1.50 g, 6.36 mmol) and perchloromethyl mercaptan (1.37 ml, 12.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.04 g, 50.9 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.10 g (62.9%) of the desired product as an oil.