Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6][CH2:5]2.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][N:4]4[C:10](=[N:1][CH:2]=[CH:3]4)[C:9]=3[CH:11]=2)[N:27]=1)=[O:19]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-c1nccn1CCC2
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)-c2nccn2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.77 (d, 2H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.34 (d, 1H), 7.09 (s, 1H), 4.22 (t, 2H), 2.81 (s, 3H), 2.73 (t, 2H), 2.48 (pent, 2H), 2.02 (s, 3H); MS (m/e) 480 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.O.[H-]>CCOCC.CCCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CN1CCC(C=O)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of ethyl 1-methylpiperidine-4-carboxylate (3.66 g, 0.0214 mole) in 20 mL of anhydrous ether at -78° under nitrogen gas was added, dropwise, 2 equivalents of diisobutylaluminum hydride (46 mL of a 20% by weight solution in hexane). After the addition (30 min.), the mixture was stirred at -78° for 2 hours. Fifty mL of water was slowly added to decompose the excess hydride. The mixture was stirred at room temperature for one hour. The ether solution was decanted and the aqueous solution was extracted with methylene chloride (3×50 mL). The combined extracts were evaporated in vacuo to give 1-methyl-4-piperidinecarboxaldehyde as a colorless liquid (2.361 g, 86.8%): IR (neat) 2940, 2850, 2790, 2740, 2680, 1725, 1440, 1450, 1380, 1280, 1145, 1090, 1070, 1040, 970, 930 and 760 cm-1 ; NMR (CDCl3) δ1.85 (m, 5H), 2.05 (m, 2H), 2.22 (s, 3H), 1.65 (m, 2H) and 9.67 (s, 1H). The NMR spectrum clearly indicated the product was the aldehyde (peak at δ9.67).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide was synthesized (80%) from 3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230), 2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 781 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.24 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[CH2:10]([C:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH2:15][CH3:16])[CH:13]=[O:14])[CH3:11].[NH4+].[Cl-]>O1CCCC1>[CH2:10]([C:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH2:15][CH3:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:14])[CH3:11]
Reactant: CCC(C=O)(CC)Cc1cccnc1
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(Cc1cccnc1)C(O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
20.4 g (0.116 mol) of 4-fluorobromobenzene in 250 ml of tetrahydrofuran are added dropwise to 2.8 g of magnesium turnings (0.166 mol) and stirring is carried out for half an hour at RT. 11 g (0.058 mol) of 2-ethyl-2-(pyrid-3-ylmethyl)-butanal in 100 ml of tetrahydrofuran are then slowly added dropwise. After 2 hours, the mixture is poured onto ice water and brought to pH 8 with saturated NH4Cl solution. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is then evaporated off. 8 g (48%) of the title compound are obtained as a viscous oil (compound No. 70 in the Table).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:33][C:34]([C:36]1[CH:41]=[C:40]([CH2:42]O)[CH:39]=[CH:38][N:37]=1)=[O:35])[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([O:33][C:34]([C:36]1[CH:41]=[C:40]([CH2:42][O:19][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:20])[CH:39]=[CH:38][N:37]=1)=[O:35])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)COC(=O)c1cc(CO)ccn1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Product: CC(C)COC(=O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (600 mg) and 4-hydroxymethylpyridin-2-carboxylic acid isobutyl ester. A colorless powder (530 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:41]=[C:42]([CH3:49])[C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:13]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[F:35][C:33]([F:34])([F:36])[C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[C:13]2[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[C:42]([CH3:49])=[CH:41][C:14]1=2
Reactant: CCOC(=O)C1CCC(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCC(C(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-cyclohexanecarboxylic acid ethyl ester (0.14 mmol) in methanol (5 mL), add 5N sodium hydroxide (14 mmol). After heating the mixture at 60° C. for 2 h, cool to room temperature and dilute with water (20 mL). Neutralize the mixture using 5M HCl and extract the organics using ethyl actate (3×5 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the crude product over silica gel, eluting with methanol/dichloromethane (0-5%) to obtain the separated cis and trans isomers. MS (ES+): 679 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=S.CC(C)N=C=NC(C)C>C(#N)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[NH:12][C:22]([NH:21][C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Yield: 56 %

Procedure:
Prepared analogously to example 1c from methyl 3,4-diamino-benzoate and 2,6-dichloro-1-isothiocyanato-benzene with DIC in acetonitrile. Yield: 56%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: COc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 89 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(4-methoxy-phenyl)-ethyl]-amine in 1 ml DMF was added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 107 mg (80%) of a white solid. MS (ISP) 441.4 (M+H)+.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].CCN(C(C)C)C(C)C.Cl.[O:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:42]5[CH2:43][CH2:44][CH2:45][O:39][CH2:40][CH2:41]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: C1CNCCOC1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/CN1CCCOCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of Example 59A (100 mg, 0.201 mmol) in DMF (2 mL) and DIPEA (0.10 mL, 0.60 mmol) was added 1,4-oxazepane hydrochloride (55 mg, 0.40 mmol). The mixture was stirred for 1 h at rt and then heated for 1 h to 50° C. The reaction mixture was directly separated by preparative HPLC. The product crystallized upon trituration with dichloromethane. The solvent was removed in vacuo to yield 83 mg (80%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26]([CH3:34])([CH3:33])[O:27][SiH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:20].Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[C:29]([SiH2:28][O:27][C:26]([CH3:34])([CH3:33])[CH:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[N:8]=[C:36]=[O:38])=[O:20])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cc(N)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
A solution of triethylamine (1.35 eq.) in anhydrous toluene was added to the amine (5)(1 eq.) and triphosgene (0.36 eq.) in anhydrous toluene under a N2 atmosphere. The reaction was finished after 2 hours. (monitored by IR, ξNCO 2265 cm1). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:18]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:11]([F:17])[CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Fc1cc(Cl)ccc1-n1cnc2ccc(Br)cc21
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4F)c3c2)cc1

Procedure:
The title compound, white solid (46 mg, 37%), MS (ISP) m/z=407.5 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-2-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate M) (100 mg, 307 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (76.0 mg, 369 μmol).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:27]2[NH:31][C:30]3[C:32]4([CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:29]=3[CH:28]=2)O1>>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:27]3[NH:31][C:30]4[C:32]5([CH2:37][CH2:36]5)[NH:33][C:34](=[O:35])[C:29]=4[CH:28]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc3c([nH]2)C2(CC2)NC3=O)OC1(C)C
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)C3(CC3)NC4=O)cccc2c1=O
Yield: 21.1 %

Procedure:
This compound (35 mg, 21% yield) as a brown solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (157 mg, 0.44 mmol) and 2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (707) (157 mg, 0.57 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (1H, br.), 7.89 (2H, t, J=7.4 Hz), 7.67 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.81 (1H, s), 5.96 (1H, s), 3.49 (3H, s), 1.50 (9H, s), 1.41 (2H, m), 1.34 (2H, m). m/z (ESI, +ve) 378.0 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1([CH3:13])[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>>[CH3:4][C:3]1([CH3:5])[C:8]2[C:7](=[C:6]([CH3:13])[CH:11]=[CH:10][C:9]=2[CH3:12])[CH2:1][CH2:2]1
Reactant: Cc1ccc(C)cc1
Reactant: C=CC(=C)C
Product: Cc1ccc(C)c2c1CCC2(C)C
Temperature: 20 °C

Procedure:
Over a period of 4.25 hours while maintaining the reaction mass at 20° C., a mixture of 540 grams (8.0 moles) of isoprene and 1590 grams (15 moles) of para-xylene is added to the reaction mass.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:15]=[N:14][N:13]([CH3:16])[C:12]=1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH2:56])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH:56][C:17]([C:12]4[N:13]([CH3:16])[N:14]=[CH:15][C:11]=4[Cl:10])=[O:19])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)cn2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
DMF (8 ml) and diisopropylethylamine (738 mg) were added to 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (916 mg, 5.7 mmol) and TBTU (1.83 g), and the mixture was stirred at r.t. (10 min). 2-Phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (400 mg, 1.9 mmol) was added and the mixture was stirred at r.t. overnight. The reaction mixture was then poured on water (35 ml), and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. The title compound (45 mg, 6.7%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40), followed by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=353.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11]C)[C:8]2[N:7]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:6]=[C:5]3[C:20]4[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:21]=4[S:22][C:3]=1[C:4]=23.Br>>[NH2:1][C:2]1[C:3]2[S:22][C:21]3[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=3[C:5]3=[N:6][N:7]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:8](=[C:9]([OH:11])[CH:10]=1)[C:4]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)cc(OC)c31)Sc1ccc(OC)cc1-2
Agent: Br
Product: CCN(CC)CCn1nc2c3c(c(N)cc(O)c31)Sc1ccc(O)cc1-2

Procedure:
Reaction of 5-amino-N,N-diethyl-3,9-dimethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine with 48% HBr as described in Example 64 gave the product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:36])[C@@H:14]4[C@@H:31]([C@H:32]([OH:34])[CH3:33])[C:30](=[O:35])[N:15]4[C:16]=3[C:17]([O:19]CC3C=CC([N+]([O-])=O)=CC=3)=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].P([O-])([O-])([O-])=O.[Na+:42].[Na+].[Na+]>C1COCC1.[Pd]>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:36])[C@@H:14]4[C@@H:31]([C@H:32]([OH:34])[CH3:33])[C:30](=[O:35])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+:42]
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 98.2 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 5.8 ml of THF and 5.8 ml of 1/15 M sodium phosphate buffer (pH 6.6) was added 98 mg of 10% Pd-C. The reactor was purged with hydrogen, and the reaction mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration through Celite, and washed with water. The filtrate was adjusted to pH 6.5 with an aqueous sodium hydrogen carbonate solution, washed with ethyl acetate, and the aqueous layer was purified by column chromatography on DIAION HP-20 (20% methanol in water) to give 38.1 mg of the title compound.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH:25]=[CH:26][C:27](=[O:29])[CH3:28])[C:21]([CH3:24])=[C:22]([CH3:23])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH:25]3[CH2:3][C:4](=[O:5])[CH2:28][C:27](=[O:29])[CH2:26]3)[C:21]([CH3:24])=[C:22]([CH3:23])[C:16]=2[O:15]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1C)CC(C)(C)O2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c(C2CC(=O)CC(=O)C2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.86 g of sodium in 37 ml of absolute methanol was added 5.6 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 8 g of the 4-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5- yl)-3-buten-2-one in 15 ml of absolute methanol, refluxed for 4 hours and then added 75 g of 6% aqueous solution of sodium hydroxide and refluxed for 4 hours. The reaction mixture was cooled to room temperature and washed three times with 50 ml of diethyl ether. 2N aqueous solution of hydrochloric acid was added drop wise into the aqueous layer until the bubble of carbon dioxide ceased. Solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 6.36 g of 5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)cyclohexane-1,3-dione as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:14](O)(=[O:16])C>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:10])[O:16][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 706.3 %

Procedure:
1,4-dicyanobenzene (6.41 g, 50 mmol) was suspended in methanol (100 ml), and sodium methoxide (0.27 g, 5.0 mmol) was added. The mixture was stirred at room temperature for 22 hours. After the reaction was completed, acetic acid (0.31 g, 5.1 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 4-cyanobenzenecarboximidate (5.77 g) as colorless powder.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccccc1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine. EXAMPLE 799
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C@H:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C[C@H]1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (34 mg, 62%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.124 mmol) and (R)-2-(tetrahydrofuran-2-yl)acetic acid
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CCCCCC>[CH3:15][Si:16]([CH3:18])([CH3:17])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 31.8 %

Procedure:
To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.0 mmol) in anhydrous DMF (50 mL), trimethylsilyl chloride (3 mL, 30.1 mmol) and triethylamine (8.3 mL, 60.2 mmol) were added at 80° C. and stirred for 10-12 h. The reaction mixture was cooled to room temperature, diluted with hexane and washed with saturated NaHCO3. Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by flash column chromatography to give tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oil (2.16 g, 32%); MS: 271 (M+).