Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)([C:19]#[N:20])[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:32].[NH4+]>>[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)([C:19]([NH2:20])=[O:32])[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 1656 parts of concentrated sulfuric acid are added portionwise 249.5 parts of 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarbonitrile. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto crushed ice and while cooling, the whole is alkalized with ammonium hydroxide. Upon stirring vigorously, the product precipitates. The supernatant aqueous phase is decanted and the residual solid product is dissolved in trichloromethane. The solution is shaken with ammonium hydroxide. The organic phase is washed with water, dried, filtered and evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off, washed with hexane and dried in vacuo, yielding 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarboxamide; mp. 179.3° C.
Reaction SMILES: Cl.CO[C:4](=N)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:12]1([CH2:19][C:20]2[S:21][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[C:5]1([C:4]2[O:26][C:25]([C:22]3[S:21][C:20]([CH2:19][N:12]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:24][CH:23]=3)=[N:27][N:28]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=N)c1ccccc1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(-c2nnc(-c3ccc(CN4CCCCCC4)s3)o2)cc1
Yield: 16.2 %

Procedure:
687 mg (4.0 mmol) of methylbenzoimidate hydrochloride was added to 7 ml of pyridine solution containing 507 mg (2.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 110 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: OC1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-2) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as white solid in 86% yield. MS: 294.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCNCC4)c3F)s2)c1
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccn2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-2-yl)piperidin-4-yl)methyl)picolinamide (compound example 47) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 638. Ret. time: 1.42 min. (Condition I); analytical HPLC Ret. time: 5.63 min (Condition H).
Reaction SMILES: [OH-].[K+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[OH:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:23])[CH:19]=[C:20]([O:14][C:8]2[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])[N:21]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Oc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1cc(Oc2c(Cl)cccc2Cl)nc(Cl)n1
Yield: 55.1 %

Procedure:
Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solution of 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). The mixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added. The mixture was stirred overnight at 60° C. The reaction was quenched with NaOH 1N solution. The aqueous layers were extracted with EtOAc several times and then the organic layers were combined and washed with NaOH 3N and saturated NaCl, dried and concentrated. The residue was recrystallized from CH2Cl2/hexane. The precipitate was filtered off and dried, yielding 5.98 g 2,4-dichloro-6-(2,6-dichlorophenoxy)pyrimidine (55%) (interm. 12). b) Reaction under Argon atmosphere. 2,4,6-trimethylaniline (0.0678 mol) was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100 ml). N,N-di(1-methylethyl)-ethaneamine (0.0830 mol) was added. The reaction mixture was stirred and refluxed for 4 days and the solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution, then dried (Na2SO4), filtered and the solvent was evaporated to give 17.1 g solid residue. This solid was dissolved in CH2Cl2:hexane (1:1; 150 ml), and the resulting solution was concentrated to 100 ml, then filtered. The residue was purified by column chromatography on KP-Sil (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated. The less polar fraction was stirred in CH2Cl2 for 3 hours and filtered, yielding 0.44 g 4-chloro-N-(2,4,6-tri-methylphenyl)-2-pyrimidinamine (intermediate 48). A second fraction was recrystallized from acetonitrile, filtered off and dried, yielding 2-chloro-1V-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine (intermediate 49).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:10][C:11]1[C:16]([CH3:17])=[C:15]([NH2:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[NH2:21]>C1(C)C=CC=CC=1.C(O)=O>[CH3:17][C:16]1[C:11]([CH3:10])=[C:12]([NH2:21])[C:13]([CH3:20])=[C:14]([CH3:19])[C:15]=1[N:18]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Cc1c(C)c(N)c(C)c(C)c1N
Reactant: CC(=O)c1ccccn1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)c(C)c(N)c(C)c1C)c1ccccn1
Temperature: 50 °C
Yield: 445.9 %

Procedure:
To a mixture of 2-acetylpyridine (0.30 ml, 0.26 mmol) and 2,3,5,6-tetramethyl-benzene-1,4-diamine (0.60 g, 0.37 mmol, 1.4 eq.) in toluene (2 ml) was added 2 drops of formic acid. The suspension was heated for three days at 50° C. The dark reddish suspension was cooled, filtered and the residue washed with cold toluene. The filtrate was evaporated, dissolved in chloroform (2 ml) and cooled to −78° C. for 0.5 hours before being filtered. Hexane was added to the filtrate and all volatiles were removed under reduced pressure to give 2,3,5,6-tetramethyl-N-(1-pyridin-2-ylethylidene)-benzene-1,4-diamine as a brown solid (0.31 g, 45%).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:44]=[C:43]([C:45]4[C:53]5[C:48](=[CH:49][CH:50]=[C:51]([NH2:54])[CH:52]=5)[N:47]([CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][O:56]5)[N:46]=4)[NH:42][C:41]=3[CH:61]=2)[CH2:33][CH2:32]1>CN(C=O)C>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:54][C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][CH:50]=2)[N:47]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][O:56]2)[N:46]=[C:45]3[C:43]2[NH:44][C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)=[CH:61][C:41]=3[N:42]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccc(N4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (3.92 mg, 0.024 mmol), HOBt (4.84 mg, 0.036 mmol), EDC (6.87 mg, 0.036 mmol) and sodium bicarbonate (2.007 mg, 0.024 mmol) was added to a solution of 3-(6-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.024 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h after and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.76-7.70 (m, 2H), 7.57 (d, 1H, J=8.8 Hz), 7.17 (m, 1H), 7.07 (dd, 1H, J=2.0 & 8.8 Hz), 5.90 (dd, 1H, J=2.0 and 9.6 Hz), 4.01 (m, 1H), 3.86 (m, 4H), 3.81 (m, 1H), 3.17 (m, 4H), 2.65 (m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 2.18-2.10 (m, 2H), 1.99 (m, 3H), 1.92-1.82 (m, 4H), 1.75 (m, 3H); ESI-MS [M+H]+: 565.17.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[CH3:21][N:22]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:41]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:41])[N:22]([CH3:21])[CH:31]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.68 (s, 3H), 7.59-7.56 (m, 1H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.96-6.92 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H). LCMS: 443.9 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([Cl:26])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([Cl:26])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:19])[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[F:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][NH:10][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cccc(F)c3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Fc1cccc2c1CNC2
Yield: 55.8 %

Procedure:
The procedure described in Reference Example 6-(3) was followed using 2.30 g of 2-(p-toluenesulfonyl)-4-fluoroisoindoline, 2.30 g of phenol, 20 ml of 48% hydrobromic acid, and 3.5 ml of propionic acid. Purification of the crude product by vacuum distillation (bath temperature: 110°-150° C., pressure: 7 mmHg) gave 604 mg of 4-fluoroisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]#[C:16][Si](C)(C)C)[C:3]=1[C:21]([F:24])([F:23])[F:22].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:16]=[CH:15]2
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)c1c(Cl)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of N-{4-chloro-3-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]phenyl}-2,2-dimethylpropanamide (Example 60B) in THF (10 mL) was treated with TBAF (3.2 mL, 1 M in THF, 3 equiv) and the reaction mixture was left to stir at ambient temperature for 14 h. Concentration was followed by partitioning between EtOAc and water. The organic portion was dried (Na2SO4), filtered, and concentrated to a waxy yellow solid. This material was used for the next reaction without further purification: MS (ESI): m/z 218 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]COS(C)(=O)=O)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 55 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available methanesulfonic acid 2-(tetrahydro-pyran-4-yl)-ethylester (described in US 2004220214) gave the title compound in 55% yield. ES-MS m/e (%): 465.2(M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.Br[CH2:18][CH2:19][CH3:20]>>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[N:9]=[C:8]([S:12][CH2:18][CH2:19][CH3:20])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CCCBr
Product: CCCSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 91 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 1-bromopropane to give the title compound in 91% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>>[NH2:15][C:16]1[C:17]([C:18]#[N:19])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:1][CH2:2][C:3]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)C1CCCCC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)C1CCCCC1

Procedure:
Prepared as in Example 22b from N-(1-hydroxy-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37c) and 2-amino-6-fluorobenzonitrile as an off-white solid (29%). MS 316 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](Cl)=[S:37])=[CH:31][CH:30]=1>COCCOCCOC>[O:35]([C:36]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[S:37])[C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: S=C(Oc1ccccc1)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of diglyme is added 0.48 ml (3.5mmole) of phenyl chlorothionoformate. The reaction is allowed to warm to room temperature and heated at 40° to 120° C. for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.C[Sn](C)(C)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[CH:9][CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: C[Sn](C)(C)c1ccco1
Reactant: Nc1nc2ccccc2n1-c1ccc(I)cc1
Product: Nc1nc2ccccc2n1-c1ccc(-c2ccco2)cc1

Procedure:
2-Amino-1-[4-(2-furyl)phenyl]benzimidazole was prepared from 1 -(2-amino-1-benzimidazolyl)-4-iodobenzene and 2-trimethylstannylfuran according to method C, mp 210°-212° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH2:8]1.S(Cl)(Cl)=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13]([O:15][CH2:4][CH2:3][CH2:18][CH3:17])=[O:14])[CH2:8]1
Reactant: O=C(O)C1=CCCN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)C1=CCCN(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
A mixture of 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (2.0 g.) and thionyl chloride (15 ml.) was heated under reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and the residue was mixed with toluene and then evaporated. n-Butyl alcohol (30 ml.) was added to the cooled residual solid and the mixture was stirred at 25° C. for 1 hour, during which time all the solid dissolved. The solution obtained was heated under reflux for 10 minutes and then excess n-butyl alcohol was removed by evaporation. The residue was recrystallised from acetone/ether to give n-butyl 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.2 g.), m.p. 160°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([O:32][CH2:30][CH3:31])=[CH:34][CH:35]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A mixture of 158 mg (0.35 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 7) and 250 μl (1.9 mmol) of 4-ethoxyaniline were heated at 90° C. for 2 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and 2M hydrochloric acid (10 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 126 mg (71%) of 3-(2,6-dichlorophenyl)-7-(4-ethoxyanilino)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 224-226° C. [Mass spectrum (ESI) MH+ =506].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C(N1C=CN=C1)([N:21]1C=CN=C1)=O>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:21])=[O:15])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Reaction time: 1 h

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1 equiv.) was dissolved to 0.2 M THF and the stirred pale yellow solution treated with carbonyldiimidazole (CDI) (1.1 equiv.). The reaction was let stir for one hour and a solution of amine (1.1 equiv 0.2 M in THF) was added over one hour and the reaction stirred overnight. The solution was concentrated, dissolved to 0.04 M in CH2Cl2 and washed sequentially with half-volumes of 0.5 M HCl, 1.0 M NaHCO3, saturated NaCl, the organic layer dried over Na2SO4 and concentrated. Flash chromatography yielded the desired 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide derivative.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][OH:14]>C(O)CCC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][OH:14])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1NCCO
Yield: 74.6 %

Procedure:
According to the procedure of B. Agai, et al., Tetrahedron, 32, 839, (1976), a solution of 1-chloro-2-nitrobenzene (50.0 g, 0.317 mol) and 2-aminoethanol (116.3 g, 1.904 mol) in nBuOH (400 mL) was heated under reflux for 6 hours. The mixture was concentrated, taken up in H2O, and extracted with ether. The organic phase was washed with brine, dried, and concentrated to give 43.1 g (75%) of an orange solid m.p. 78° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CSCCNC1=O
Yield: 66.5 %

Procedure:
N-t-Butoxycarbonyl-S-(2-aminoethyl)-L-cysteine (5.0 g) and N-hydroxysuccinimide (2.6 g) are dissolved in 500 ml of DMF. With cooling in an ice-bath, a solution of dicyclohexylcarbodiimide (4.7 g) in 10 ml of DMF is added dropwise over a period of 15 minutes. The reaction mixture is kept in a 4° room for 10 days. The solvent is then removed by lyophilization. The crude product is extracted into chloroform. Repeated chromatography on silica gel (20:1 chloroform-methanol) affords the pure product (3.1 g). The NMR spectrum is consistent with the assigned structure. A pure sample is obtained by recrystallization (ether-methanol) and analyzes for C10H18N2O3S.