Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=1>>[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)=[C:22]([CH3:28])[CH:21]=1
Reactant: Cc1cc(Cl)cc(C)c1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cc(Cl)cc2C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 4-Chloro-2,6-dimethyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 8.73 (br, 1H), 7.72 (br, 1H), 7.19 (s, 2H), 7.03-6.95 (2H), 6.36 (br, 1H), 3.95 (t, 2H), 3.85 (s, 3H), 2.96 (t, 2H) and 2.18 (s, 6H); MS (ESI) (M+H)+ 382.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[CH:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=1)=[O:4].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[N:10][C:9]=2[CH:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=1)=[O:4]
Reactant: CCN=C=O
Reactant: COC(=O)c1cc(-c2cccnc2)cc2nc(N)sc12
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Temperature: 125 °C

Procedure:
A stirred mixture of 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (20 mg, 0.07 mmol), ethyl isocyanate (0.03 ml, 0.35 mmol) and dibutyltindiacetate (2 drops) in anhydrous 1,4-dioxane (1.5 ml) was heated by microwave irradiation in a CEM Discover reactor at 125° C. for 1 h. After cooling to ambient temperature, the 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester was isolated by Preparative HPLC as a white solid (7.4 mg, 30%).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C.[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=N)[NH2:12]>C(O)C>[CH2:1]([NH:6][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[NH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: N=C(N)NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCNC(=N)NC(N)=S
Temperature: 85 °C

Procedure:
To a one liter, 3-necked round bottom flask which was equipped with a mechanical stirrer, thermometer, and reflux condenser were added absolute ethanol (180 ml.) and pentylamine (100.0 g., 1.15 mol). The amine solution was cooled in an ice bath while glacial acetic acid (68.9 g., 1.15 mol) was slowly added. Amidinothiourea (90.37 g., 0.76 mol) was added and then the mixture was heated to reflux (85° C.). After 24 hours at reflux, HPLC analysis of the reaction solution indicated that title product (72.6 area %) had formed and that residual amidinothiourea (8.5 area %) remained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:24][CH3:25])[CH2:12][CH:11]([CH2:13][CH2:14][S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:23])[CH:9]=2)[O:4]1)[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]O)[CH3:27].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([C:3]1([CH2:1][CH3:2])[CH2:12][CH:11]([CH2:13][CH2:14][S:15]([NH:18][CH2:19][C:20]([O:22][CH2:27][CH2:26][O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])=[O:21])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:23])[CH:9]=2)[O:4]1)[CH3:25]
Reactant: CCC1(CC)CC(CCS(=O)(=O)NCC(=O)O)c2cc(C)ccc2O1
Reactant: CCOCCOCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOCCOCCOC(=O)CNS(=O)(=O)CCC1CC(CC)(CC)Oc2ccc(C)cc21
Yield: 44.2 %

Procedure:
A solution of 0.5 g (1.35 mmol) of [(2,2-diethyl-6-methylchroman-4-yl)ethylsulfonylamino]acetic acid, 0.2 g (1.5 mmol) of diethylene glycol monoethyl ether, 0.31 g (1.5 mmol) of DCC and 2 mg (0.01 mmol) of DMAP in 7 ml of methylene chloride is stirred overnight at RT. It is washed successively with 5% strength acetic acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. After subsequent purification by chromatography using cyclohexane/EA 4:1, 0.29 g of 2-(2-ethoxyethoxy)ethyl [(2,2-diethyl-6-methylchroman-4-yl)ethylsulfonylamino]acetate is obtained as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:9]=[CH:8][C:7]=1[N+:22]([O-])=O)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[NH2:22])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cc(Nc2cccc(N)c2)ccc1N
Reaction time: 20 h

Procedure:
To a solution of [2-nitro-5-(3-nitro-phenylamino)-phenyl]-acetic acid ethyl ester (0.36 g, 1.0 mmol) in methanol (10 ml) is added Pd/C (10%, wet, 0.1 g). The reaction is placed under a hydrogen balloon and stirred for 20 hours. The catalyst is filtered and the solvent is removed to give the desired compound. LC-MS: 286.1 (MH+).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:13][C:12]2[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=2[O:4]1.O.Cl[CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][O:21][CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([O:21][CH2:20][CH2:19][C:18]([CH3:25])=[CH:17][CH2:16][O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]2[O:13][CH2:3][O:4][C:5]=2[CH:6]=1)([CH3:24])[CH3:23]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(=CCCl)CCOC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=CCOCc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
8.0 g (0.2 mol) of sodium hydroxide are added to a solution of 30.4 g (0.2 mol) of 3,4 -methylendioxy-benzylalcohol in 300 cc of benzene. The mixture is heated while stirring vigorously and kept at reflux temperature whereby the water condensing in a refrigerator is separated by means of a water separator. After 24 hours 35.3 g (0.2 mol) of 1-chloro-5-isopropoxy-3-methyl-2-pentene are added dropwise during the course of 1 hour and the mixture is stirred under reflux for a further 16 hours.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O>C(O)C>[F:4][C:5]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[N:2][OH:3]
Reactant: O=Cc1cccc(I)c1F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1cccc(I)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
A 50% aqueous solution of hydroxylamine hydrochloride (9 mL, 64.8 mmol) was added to a stirred suspension of 2-fluoro-3-iodobenzaldehyde (preparation 22d, 2.10 g, 8.4 mmol) in ethanol (10 mL) and the mixture was warmed slightly until a solution was formed. After stirring for 3 days at room temperature, the mixture was concentrated in vacuo and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (2.15 g, 97%) as a solid.
Reaction SMILES: [I:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3([C:11]4[N:12]([N:13]=[C:14]([C:16](OCC)=[O:17])[CH:15]=4)[C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.[OH-].[NH4+:24]>O1CCOCC1.C(OCC)(=O)C.O>[I:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3([C:11]4[N:12]([N:13]=[C:14]([C:16]([NH2:24])=[O:17])[CH:15]=4)[C:4]=2[CH:3]=1)[CH2:10][CH2:9]3
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC21CC1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC21CC1
Temperature: 110 °C

Procedure:
A solution of ethyl 9-iodo-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxylate (313 mg, 0.76 mmol) in ammonium hydroxide (3 mL) and dioxane (2 mL) was sealed in a 20 mL microwave vial and heated at 110° C. behind a blast shield. The mixture was cooled to room temperature, diluted with ethyl acetate and water and washed with sodium bicarbonate solution. The organics were dried over sodium sulfate and concentrated by rotoevaporation to give the titled compound which was used without purification in subsequent operations. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.1 Hz, 1H), 7.83 (br s, 1H), 7.61 (dd, J=8.5, 2.2 Hz, 1H), 7.33 (br s, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 4.22 (s, 2H), 1.10-0.96 (m, 4H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>C(Cl)Cl>[CH3:21][N:22]([CH3:23])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: CNC
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) is added in portions over a period of 1 hour to a stirred solution of N,N-dimethylamine (18.9 g) in methylene chloride (100 ml), cooled to 0° C. The mixture is stirred for 1 hour at 0° C. The solution is evaporated under reduced pressure. The residue is taken up in methylene chloride (100 ml). The organic phase is washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Title compound isolated as an off-white solid (69 mg, 48%). LCMS 534.14 (M+H), HPLC purity 95%, 1H-NMR (CDCl3, 400 MHz) δ 10.96 (s, 1H), 9.11 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.54-7.49 (m, 2H), 7.26 (d, 2H), 6.69 (d, J=8.2 Hz, 1H), 4.08-4.00 (m, 1H), 2.35 (dd, J=6.9 Hz, 2H), 2.05 (dd, J=7.3 Hz, 2H), 1.30 (s, 6H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:7])[CH3:6].[Br:18]Br>>[Br:18][C:16]1[CH:17]=[C:8]([C:5](=[O:7])[CH3:6])[CH:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Br)c2c(c1)CCCC2
Temperature: 25 °C

Procedure:
To AlCl3 (9.9 g, 75 mmol) is added dropwise 6-acetyltetralin (5.25 g, 30 mmol) under mechanical stirring at RT. After 20 minutes at 70° C. the reaction is cooled to RT and treated in small portions with Br2 (5.76 g [=1.86 ml], 36 mmol) over a period of 30 minutes. After that the mixture is stirred for further 60 minutes at 85° C. After cooling down to RT and addition of ice-water (450 ml) the compound is extracted with methylene chloride and purified on silica gel using a mixture of cyclo-hexane/ethyl acetate 2/1 to 1/1 obtaining the product as a pale yellow solid.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C(C)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:38]([O:42][C@@H:43]([C:49]1[C:67]([CH3:68])=[CH:66][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]4[N:62]=[N:63][C:64]([CH3:65])=[C:58]4[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[C:44]([O:46]CC)=[O:45])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C@@H:43]([C:49]1[C:67]([CH3:68])=[CH:66][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]4[N:62]=[N:63][C:64]([CH3:65])=[C:58]4[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[C:44]([OH:46])=[O:45])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4nnc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccn4nnc(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-[1,2,3]triazolo[1,5-a]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.0 (M+H+); Found: 521.2 (M+H+). NMR (400 MHz, CD3OD) δ 8.87 (d, J=7.4 Hz, 1H), 8.43 (s, 1H), 7.86 (s, 1H), 7.78 (dd, J=7.4, 1.8 Hz, 1H), 7.73-7.67 (m, 1H), 7.65-7.56 (m, 3H), 5.27 (s, 1H), 2.63 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]=[CH:23][C:22]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CS(C)=O>[O:14]1[C:15]2[C:22]3[CH:23]=[CH:24][O:25][C:21]=3[CH:20]=[CH:19][C:16]=2[O:17][CH2:18][CH:13]1[CH2:12][N:26]1[CH2:27][CH:28]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4occc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4occc4c3O2)C1
Temperature: 25 °C

Procedure:
A solution of 0.40 g (1.1 mmole) of (2R)-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 4 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform to give 0.27 g of the (S)-enantiomer of the title compound as a white solid, m.p. 208-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH2:8][C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(Cl)cc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2

Procedure:
9.00 g (0.042 mol) of 6,7-dichloro-3,4-dihydro-2(1H)-naphthalenone and 0.3 g of p-toluenesulfonic acid are dissolved in 200 ml of pyridine, 3.5 ml (0.042 mol) of pyrrolidine are added dropwise and the mixture is boiled under reflux for 2 hours. Distillation of the solvent in a vacuum, addition of 200 ml of ether and filtering off the crystals formed yields 1-(6,7-dichloro-3,4-dihydro-2naphthyl)pyrrolidine with melting point 141°-142°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[N:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=2)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:24]=[N:23][CH:22]=1
Reactant: O=C(NCc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: OB(O)c1cncnc1
Product: O=C(NCc1cccc(-c2cncnc2)c1)OC1CN2CCC1CC2
Yield: 54.2 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromobenzylcarbamate (203 mg, 0.600 mmol), pyrimidin-5-ylboronic acid (149 mg, 1.2 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous semi-solid (110 mg, 54%). 1H NMR (500 MHz, CDCl3) δ 9.20 (s, 1H), 8.94 (s, 2H), 7.51 (m, 3H), 7.40 (m, 1H), 5.62 (m, 1H), 4.81 (m, 1H), 4.50-4.40 (m, 2H), 3.30 (m, 1H), 2.97-2.65 (m, 5H), 2.12 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.69 (m, 1H), 1.65-1.56 (m, 1H), 1.50-1.42 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 157.6, 156.2, 154.9, 140.1, 134.7, 134.1, 129.8, 128.2, 126.2, 70.9, 55.2, 47.2, 46.2, 44.8, 25.2, 23.8, 19.0 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.22 min; (M+1) 339.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1nc(-c2sc(NC(=O)C3CCCCC3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and cyclohexanecarbonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.C(OC(Cl)=O)C(C)C>O1CCCC1.C(N(CC)CC)C>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)cc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid in tetrahydrofuran (50 mL) and triethylamine (4.7 mL) was cooled to 0° C. and isobutylchloroformate (4.02 mL) was added dropwise and the solution was stirred at 0° C. for 2 hours, when it was filtered into a stirred solution of sodium borohydride (3.14 g) in ice/water (50 mL). The mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature. It was acidified with 2M hydrochloric acid, evaporated to half volume, and the resulting product was collected, washed with water and dried in vacuo, to give a white solid (4.5 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.CN([CH:36]=[O:37])C>C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:6]([F:15])=[C:5]([CH:4]=1)[CH:36]=[O:37])[CH3:2]
Reactant: CCc1ccc(F)c(N2CCOCC2)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(N2CCOCC2)c1
Temperature: -45 °C
Reaction time: 0.33 h

Procedure:
To a solution of Intermediate 230.1 (102 mg, 0.487 mmol) and PMDTA (0.132 mL, 0.634 mmol) in 3 mL THF at −78° C., was added BuLi (1.6 M in THF, 0.365 mL, 0.584 mmol). The mixture was allowed to warm to −45° C. over 20 min, then was recooled to −78° C. DMF (75 μL) was added, then the reaction mixture was removed from the cooling bath and stirred 20 min before being quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 35% EtOAc/hexanes gradient) to afford 77 mg of Intermediate 406.1. LCMS (2 min gradient) RT=1.47 min, 238.18 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3,4-dichlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 274°-276° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[CH:31][C:32]=1[NH:33][C:34]1[S:35][C:36]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)=[CH:37][N:38]=1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:44][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]2[S:35][C:36]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)=[CH:37][N:38]=2)=[C:27]([CH3:26])[CH:28]=1
Reactant: Cc1cc(O)ccc1Nc1ncc(-c2ccsc2)s1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(OCCN(C)C)ccc1Nc1ncc(-c2ccsc2)s1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 3-methyl-4-(5-thiophen-3-yl-thiazol-2-ylamino)-phenol and using (2-chloroethyl)-dimethylamine hydrochloride. The title compound: ES-MS: 360.0 [M+H]+; single peak at tR=2.78 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 75/25).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23]C)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=O)C=1.ClC(Cl)(Cl)C([N:42]=C=O)=O.[N-]=C=O>CO>[NH2:42][C:9]1[C:8]2[N:17]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [N-]=C=O
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Reaction time: 72 h
Yield: 103.8 %

Procedure:
A modification of the methods described in Part B of Example 60 was used to treat ethyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (11.0 g, 31 mmol) with mCPBA (13.6 g of 77% pure material), followed by trichloroacetyl isocyanate (4.4 mL, 37 mmol). The reaction with the isocyanate was stirred for 1.5 hours before the addition of additional trichloroacetyl isocyanate (4.4 mL) and stirring for three days. Additional trichloroacetyl isocyanate (0.5 mL) was added, and the reaction was stirred for four hours. After the addition of methanol (50 mL), the solution was stirred overnight, and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (150 mL), and the solution was washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL ammonium hydroxide per liter of eluent) to provide 11.4 g of methyl 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as a semi-solid.