Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2([C:27]#N)[CH2:14][CH2:13][N:12]([CH:15]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=[CH:24]4)[CH:20]=[CH:19][CH:18]=[C:17]5[CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(OCC)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH:15]1([N:12]2[CH2:11][CH2:10][C:9]3([N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:32](=[O:33])[CH2:27]3)[CH2:14][CH2:13]2)[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1
Reactant: N#CC1(Nc2cccc(Cl)c2)CCN(C2Cc3cccc4cccc2c34)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3Cc4cccc5cccc3c45)CC2)N1c1cccc(Cl)c1

Procedure:
Reaction of (RS)-4-(3-chloro-phenylamino)-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, white solid, m.p. 214° C. and MS: m/e=403.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17].Cl>N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:13]([Cl:12])[CH:14]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (5 ml) and 3,4-dichlorobenzoylchloride (0.85 g) was added at room temperature with stirring. The mixture was stirred for 5 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-bromo-4-trifluoromethylthiazol-2-yl)-3,4-dicloro-benzamide (1.29 g), m. p. 191-192° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12](=[O:15])[CH2:13][OH:14])[CH2:8][CH2:9][CH3:10].Cl.C(=O)(O)[O-].[Na+]>>[CH2:7]([O:11][C:12](=[O:15])[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][CH3:10]
Reactant: C1=COCCC1
Reactant: CCCCOC(=O)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
84 g of 3,4-dihydro-2H-pyran and 132 g of glycolic acid butyl ester are dissolved at room temperature. To this solution are added 0.5 ml of concentrated hydrochloric acid, whereupon the temperature immediately rises to 90°. The solution is cooled to room temperature and stirred for 2 hours. After the addition of 1 g of sodium bicarbonate, the crude product is distilled under 17 Torr to obtain 2-(tetrahydropyran-2-yloxy)-acetic acid butyl ester, B.P. 127°/17 Torr.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>>[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:11]=3)[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1ccncc1N=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2ccncc2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17A and 63 mg (0.36 mmol) of 3-methylphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 88 mg (48% of theory) of product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[CH:31][N:30]=[CH:29]1>>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:40]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2ccnc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-1-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol/ammonia=10:1:0.01) C27H22N4O3
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 472 [M+H]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[H-].[Na+].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl>CN(C)C=O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 0.75 h

Procedure:
A 1.10 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 25 ml of dimethylformamide. A 213 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A 480 mg portion of 2-dimethylaminoethyl chloride in 2 ml of dimethylformamide was added and the sealed mixture was stirred overnight. The solvent was removed at 60° C. and the residue partitioned between 25 ml of water and 50 ml of ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with 1N sodium hydroxide, dried, filtered and evaporated. The residue was taken up in 20 ml of chloroform, boiled down to 1/3 volume and hexane added to turbidity. The mixture was allowed to stand overnight, giving 400 mg of the desired product as beige crystals, mp 108°-110° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][CH2:20][C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][C@H:24]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17]1)(=O)C1C=CC=CC=1.O>C(OCC)C>[Si:44]([O:43][C@H:24]1[CH2:23][C@@H:22]2[C@:34]([CH3:42])([CH2:35][CH2:36][C@H:37]3[C@H:21]2[CH2:20][CH:19]=[C:18]2[C@:38]3([CH3:41])[CH2:39][CH2:40][C@H:16]([OH:15])[CH2:17]2)[C@H:25]1[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46]
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
To a suspension of lithium aluminium hydride (4.5 g, 120 mmol) in diethyl ether (700 mL) was added, dropwise 16β-(tert-butyldimethylsilyloxy)cholest-5-en-3β-yl benzoate (8.1 g, 12 mmol) in diethyl ether (50 mL). After stirring at room temperature for 15 minutes and at 40° C. for 0.5 hour, water was added. The inorganic impurities were removed by filtration through Celite, and after removal of solvent under reduced pressure the residue was purified by flash chromatography to give 16β-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (6.7 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[CH3:36][C:37]([CH3:39])=O.[BH3-]C#N.[Na+]>C(O)C>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH:37]([CH3:39])[CH3:36])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: CC(C)=O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 29.1 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-pentaene (140 mg, 0.300 mmol) and acetone (174 mg, 3.0 mmol) in ethanol (10 mL) was added Ti(Oi-Pr)4 (171 mg, 0.60 mmol). After being stirred at 20° C. for 20 min, NaBH3CN (37 mg, 0.60 mmol) was added and stirred at 20° C. for 24 h. The solvent was removed and several drops of water were added. The solid was filtered off and the filtrate was evaporated to afford the crude product, which was purified prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to give racemic 268 (45 mg, 29% yield). LCMS (ESI): RT=5.41 min, m/z: 515.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09 (dd, J=8.5, 1.5 Hz, 1H), 6.94 (s, 1H), 5.90-5.82 (m, 1H), 4.53 (s, 4H), 3.90 (s, 3H), 3.11 (m, 1H), 3.10-2.66 (m, 3H), 2.50 (t, J=2.0 Hz, 1H), 2.26 (s, 3H), 2.08 (m, 1H), 1.80-1.20 (m, 10H), 0.95-0.92 (m, 6H)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:31])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 40 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 83 (40% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.79 and 3.04 (2t, 2H), 3.59 and 4.22 (2t, 2H), 4.47 and 5.09 (2s, 2H), 6.32 and 6.82 (2d, 1H), 6.89 and 7.08 (2d, 1H), 7.58-7.69 (m, 1H), 7.93-8.05 (m, 2H), 8.31-8.35 (m, 1H), 8.56 and 8.61 (2s, 1H), 9.04 (s, 1H); MS (ESI) m/z 403 ([M+H]+).
Reaction SMILES: Br[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[CH:6]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[CH:6]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Br)c1
Product: O=[N+]([O-])c1c[nH]c(-c2ccc(F)cc2)c1
Yield: 40 %

Procedure:
2-Bromo-4-nitro-1H-pyrrole (886 mg, 4.64 mmol) synthesized in Reference Synthesis Example 244 and 4-fluorophenylboronic acid (779 mg, 5.57 mmol) were used to obtain the title compound (383 mg, yield 40%) by synthesis in a similar manner to Reference Synthesis Example 139.
Reaction SMILES: I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1.[C:28]([NH:36][OH:37])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>ClCCl>[CH:24]12[CH2:23][CH:27]([CH:26]=[CH:25]1)[N:36]([C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])[O:37]2
Reactant: O=C(NO)c1ccccc1
Reactant: C1=CCC=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1OC2C=CC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Tetra-n-butylammonium periodate (17.3 g, 39.9 mmol) was added to a solution of freshly cracked cyclopentadiene (4.00 g, 60.6 mmol) in dichloromethane (150 cm3). Benzohydroxamic acid (5.50 g, 40.1 mmol) was then added portionwise over 5 minutes and the solution was stirred overnight at room temperature. Upon completion of reaction, the organic solution was washed successively with sodium thiosulfate (10% aq. soln., 2×400 cm3) and sodium hydrogen carbonate (sat'd. aq., 500 cm3), then dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude black oil. Flash chromatography (SiO2, 40% ethyl acetate in petrol) gave the bicyclic adduct 7 (6.23 g, 31.0 mmol, 78%) as a light brown oil, which solidified upon standing at room temperature; δH (250 MHz, CDCl3) 7.75 (2H, m, ArH), 7.52–7.37 (3H, m, ArH), 6.50 (1H, m, CH═CH), 6.37 (1H, m, CH═CH), 5.35 (1H, m, CHNBz), 5.28 (1H, m, CHON), 2.13 (1H, dt, J 8.6 & 1.9 Hz, CHH), 1.84 (1H, m, CHH).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClC[CH2:26][N:27](C)[CH3:28].[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]([CH3:28])[CH3:26])=[CH:11][N:12]=1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN1CCC(=O)N(C)c2cnc(Cl)nc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising 2 chloroethyldimethylamine hydrochloride (Aldrich; 52 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (84 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[NH:35]([CH3:37])[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([CH3:37])[CH3:36])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: CNC
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Solvent: C1CCOC1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)N(C)C)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (Example 295B) (0.037 g, 0.07 mmol) and Me2NH (2.0 mL), and THF (5.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.025 g, 66% yield): MS (ES) m/z 515 (M+).
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH3:20][NH2:21]>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:21]([CH3:20])[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Reactant: CN
Product: Cc1cc2c(n1C)C(C)CN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl-5-methyl-4-piperidone may be reacted with methylamine to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2ccc(OC(F)F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 111.5 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([N:12]([CH3:18])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CN(c1nccs1)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1nccs1)C1CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of 166 mg (0.62 mmol) of 1-Boc-3-(methyl(thiazol-2-yl)amino)azetidine in DCM (5 ml) was combined with 2.5 ml of TFA and stirred for 3 h at RT. The mixture was then evaporated under a vacuum. The residue was redissolved with water and washed with ether. The aqueous phase was adjusted to pH 11 with a 20% strength aq. NaOH soln. and saturated with common salt. The mixture was then extracted with chloroform and the organic phase was dried over MgSO4 and filtered. After removal of the solvents under a vacuum, 102 mg (0.60 mmol, 97%) of 3-(methyl(thiazol-2-yl)amino)azetidine were obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[CH:20]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:12]([C:9]3[CH:10]=[CH:11][C:5]4[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[CH2:32][CH2:31]1)=[CH:20]2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (21 mg, 0.09 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (13 mg, 0.10 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol, 1.15 eq) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as a white solid (30 mg, 59% yield).
Reaction SMILES: [F:1][C:2]([F:14])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[CH3:3]>CCO.[Ni]>[F:1][C:2]([F:14])([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(F)(F)Oc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CC(F)(F)Oc1ccc(N)cc1

Procedure:
A solution of 1-(1,1-difluoroethoxy)-4-nitrobenzene (Stage 30.4, 2.95 g, 13.94 mmol) in EtOH (100 mL) was hydrogenated (Raney Ni 1.0 g; 26.5 h at RT). The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude title product as a brown oil. HPLC (Condition 5) tR=4.5 min, UPLC-MS (Condition 3) tR=0.74 min, m/z=174.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:19]2[CH:20]=[CH:21][C:22]3[CH2:23][C@H:24]4[C@@H:29]([C:30]=3[CH:31]=2)[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:29]4[C:30]5[CH:31]=[C:19]([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)[CH:20]=[CH:21][C:22]=5[CH2:23][C@H:24]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc(-c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)cc1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(-c4ccccc4)ccc3C[C@@H]21
Yield: 63 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 63% of theory; LC (method 1): tR=3.28 min; Mass spectrum (ESI+): m/z=394 [M+H]+.