Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]2[CH2:7][CH2:8][C:9]([CH3:19])([CH3:18])[C:10]=2[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:14]([C:12]1[CH:13]=[C:5]([OH:4])[C:6]2[CH2:7][CH2:8][C:9]([CH3:19])([CH3:18])[C:10]=2[CH:11]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Oc1cc(C(C)(C)C)cc2c1CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(O)c2c(c1)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of the above indane 14 (0.36 g, 1.37 mmol) dissolved in 15 rnd. MeOH was added solid K2CO3 (0.38 g, 2.74 mmol). The reaction mixture was allowed to stir overnight at room temperature. MeOH was evaporated and the residue was diluted with 10 mL of water. The aqueous layer was then acidified with 5% HCl until pH=4 or 5. Aqueous layer was extracted with EtOAc (2×10 mL). Then the organic layer was washed with saturated NaCl and dried with Na2SO4. Organics were concentrated in vacuo to provide 0.25 g of the 6-t-butyl-1,1-dimethyl-indan-4-ol intermediate in 84% yield that was used directly into the next step. A solution of the above indane (0.25 g, 1.15 mmol) dissolved in 2 mL of dry pyridine was cooled to 0° C. Trifluoroacetic anhydride (0.36 mL, 2.13 mmol) was slowly added. Resulting mixture was allowed to warm to room temperature and was allowed to stir overnight. Reaction mixture was poured into 15 mL of water and extracted with ether (2×10 mL). Ether extract was sequentially washed with water (10 mL), 10% aq. HCl (2×10 mL), water (10 mL), and saturated NaCl. Organics were then dried with Na2SO4 and concentrated in vacuo to give 6-t-butyl-1,1-dimethyl-indan-4-ol triflate (15) as a clear oil in 77% yield. 1H NMR (400 MHz, CDCl3) δ7.13 (d, J=1.4 Hz, 1H, aromatic), 7.01 (d, J=1.2 Hz, 1H, aromatic), 2.95 (t, J=7.2 Hz, 2H, aliphatic CH2), 1.97 (t, J=7.2 Hz, 2H, aliphatic CH2), 1.31 (s, 9H, aliphatic 3CH3) 1.27 (s, 6H, aliphatic 2CH3).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@:7]([OH:55])([C@@H:15]([C:33](=[O:54])[NH:34][C@H:35]([C:48]1[O:49][C:50]([CH3:53])=[CH:51][N:52]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]#[C:46][CH3:47])=[CH:39][CH:38]=1)/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10]C(C)(C)C)=[O:9])(=O)C>C(O)=O>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@H:35]([NH:34][C:33]([C@@H:15](/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@:7]([OH:55])([CH2:6][CH2:5][OH:4])[C:8]([OH:10])=[O:9])=[O:54])[C:48]2[O:49][C:50]([CH3:53])=[CH:51][N:52]=2)=[CH:38][CH:39]=1)[C:45]#[C:46][CH3:47]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)c2ncc(C)o2)cc1
Solvent: O=CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)c2ncc(C)o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl (E)-(2S,3S)-2-(2-acetoxy-ethyl)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-(5-methyl-oxazol-2-yl)-ethylcarbamoyl]-2-hydroxy-12-oxo-nonadec-4-enoate (4.0 mg) was dissolved in formic acid (0.5 mL), and the mixture was stirred at room temperature for 24 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Yield: 93 %

Procedure:
To a suspension of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.51 g, 2.00 mmol) and potassium carbonate (0.49 g, 3.54 mmol) in acetone (30 mL) was added benzyl bromide (0.30 mL, 0.25 mmol). The reaction mixture was heated to reflux for 16 hours. The solvent was removed in vacuo, and the residue was washed with water (100 mL) and hexanes (30 mL) to afford the title compound in 93% yield (0.65 g): mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 4.40 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 346.0 (M+1).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]>>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCCO
Product: N#Cc1c(OCCCO)cccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Prepared as in Example 215c from propane-1,3-diol and 2,6-dinitrobenzonitrile in 61% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.93 (m, 2H), 3.56-3.61 (m, 2H), 4.30 (t, J=6.4 Hz, 2H), 4.61 (t, J=5.2 Hz, 1H), 7.71-7.74 (m, 1H), 7.85-7.91 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@H:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([OH:50])=[O:39])=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O)cc1
Product: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O[C@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 4-(2-benzyl-benzo[b]thiophene-3-yl)-4″-methoxy-[1,1′;3′,1″]terphenyl-4′-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 82-84° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25](Br)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CCOC(C)=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>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25]([C:37]4[O:38][CH:39]=[CH:40][CH:41]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 366 mg (0.76 mMol) 1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 17: a) in 7 ml degassed DMF under a N2-atmosphere are added 174 mg (0.15 mMol) of Pd[P(C6H5)3]4 and 0.6 ml (1.9 mMol) of 2-tributylstannyl-furan (Aldrich). After 4 h stirring at 100° C., the reaction mixture is diluted with EtOAc and washed with NaHCO3 solution. The aqueous layers are extracted twice with EtOAc, the organic phases washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2; CH2Cl2/Et2O 7:3) and crystallization from DIPE yields the title compound. mp: 180-182° C.; ES-MS: (M+H)+=465; HPLC(Grad20-100) tRet=15.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:10][CH:9]1[C:11]([O:13]CC)=O.[C-]#[N:17].[Na+].N>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:10][CH:9]1[C:11]([NH2:17])=[O:13]
Reactant: [C-]#N
Reactant: CCOC(=O)C1CC1OC1CCCCO1
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1CC1OC1CCCCO1

Procedure:
In an autoclave, a solution of 0.25 mol of the compound obtained in Step 2, 2 g of sodium cyanide, 300 ml of a 2N solution of ammonia in methanol and 80 ml of liquid ammonia is heated at 65° C. for 5 days and is then concentrated to dryness. The residue is taken up in a mixture of dichloromethane/saturated potassium carbonate solution, filtered over Celite and then treated in conventional manner. After evaporating under reduced pressure, the residue is triturated in petroleum ether, filtered, rinsed and dried, allowing the expected product to be isolated.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH2:33][CH:34]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=1)[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.C(N(CC)CC)C.[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70](O)=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]>C(Cl)Cl>[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70]([N:32]([CH2:33][CH:34]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)[CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:31][CH2:30][O:29][CH3:28])=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]
Reactant: COCCNCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2.6 g of BOP are added to a solution cooled at 0° C. of 1.9 g of the product prepared in step 2, 1.2 g of triethylamine and 0.96 g of 3-isopropoxyphenylacetic acid in 50 ml of CH2Cl2. The reaction mixture is stirred for one hour and is then concentrated under vacuum. The residue is taken up in ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum. 2.2 g of the expected product is obtained, which is directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][NH:19][CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][N:19]([C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1)[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Nc1ccc(Cl)nn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nn1)C2
Temperature: 130 °C
Yield: 30.1 %

Procedure:
In a mortar and pestle 6-chloro-pyridazin-3-ylamine (100 mg, 0.772 mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (180 mg, 0.849 mmol) were grounded together, placed in a sealed tube and heated to 130° C. for 16 h. The reaction was allowed to cool to room temperature and then the contents were dissolved in a minimal amount of dichloromethane. The crude product was purified by silica gel chromatography using a 0-50% ethyl acetate heptane gradient which gave 3-(6-amino-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70.7 mg, 0.232 mmol) in 30% yield.
Reaction SMILES: N1C2C=NNC(=O)C=2C=C[CH:2]=1.[C:12]([C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[NH2:13].CS(Cl)(=O)=O>>[C:12]([C:15]1[C:16]([C:21]([O:23][CH3:2])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:13]
Reactant: NC(=O)c1cccnc1C(=O)O
Reactant: O=c1[nH]ncc2ncccc12
Agent: CS(=O)(=O)Cl
Product: COC(=O)c1ncccc1C#N

Procedure:
Using a procedure similar to that described for 6H-pyrido[2,3-d]pyridazin-5-one derivatives (Examples 5), 3-carbamoylpicolinic acid (1.5 mmol) was reacted with excess MsCl (4.0 mmol) to yield methyl 3-cyanopicolinate (1.2 mmol). Methyl 3-cyanopicolinate (1.2 mmol), Sc(OTf)3 (0.02 mmol), and diaminopropane (3.0 mmol) were combined and heated at 80° C. for 1 h to yield 7.8-dihydro-6H-1,5,8a-triaza-fluoren-9-one, which was treated with excess hydrazine hydrate (5.0 mmol) in EtOH at RT to yield compound 5-(3-amino-propylamino)-7H-pyrido[2,3-d]pyrido[2,3-d]pyridazin-8-one (0.75 mmol) as a yellow solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:36])([F:38])[F:37])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.28 g, 54%). MS (ISP) 523.1 [(M−H)−]; mp 247° C.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([CH:35]([CH3:37])[CH3:36])=[N:32][C:31]=2[C:38]2[CH:39]=[CH:40][C:41]([F:51])=[C:42]([NH:44]C(=O)OCC=C)[CH:43]=2)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([CH:35]([CH3:37])[CH3:36])=[N:32][C:31]=2[C:38]2[CH:39]=[CH:40][C:41]([F:51])=[C:42]([CH:43]=2)[NH2:44])[CH:27]=[CH:26][N:25]=1
Reactant: C=CCOC(=O)Nc1cc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)ccc1F
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Yield: 90.1 %

Procedure:
In a procedure analogous to Intermediate 13, 1.1 g (92% yield) of the title compound was prepared from 2-propen-1-yl {5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (1.5 g, 3.5 mmol) (Intermediate 41). MS (ES+) MS: 349.27 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of methyl 4-formylbenzoate (25 g) in methylene chloride (250 mL) is added successively N,N-dimethylethylenediamine (67 g), acetic acid (87 mL), and sodium triacetoxyborohydride (50.6 g). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and to the residue is added a saturated potassium carbonate solution. The mixture is extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]-benzoate (31.9 g, yield; 89%) as a colorless oil. MS (APCI) m/z: 237 [M+H]+
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[Li+].[BH4-]>CO>[Cl:29][C:28]1[C:23]([CH2:22][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cc1cccnc1CN(Cc1ccc(C#N)cc1CO)Cc1ncccc1Cl
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a cold (0° C.) solution of 2-{[(3-Chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.314 g, 0.75 mmol) in MeOH (7 mL) was added LiBH4 (106 mg, 4.89 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (25 mL) and 1.0 N NaOH (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.19 g (65%) of 4-{[(3-Chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-3-hydroxymethyl-benzonitrile as a white foam. The white foam from above (0.19 g, 0.48 mmol) was dissolved in NH3 saturated MeOH (10 mL), treated with Raney nickel (80 mg), and placed under 50 psi H2 on a Parr shaker, for 19 h. The mixture was filtered through celite and the cake was washed with methanol. The eluant was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.15 g (82%) of a 1:1 mixture of (5-aminomethyl-2-{[(3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-phenyl)-methanol and (5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenyl)-methanol as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(C(F)(F)F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (63 mg, 65%), MS (ISN) m/z=388.4 [(M−H)+], mp 347° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:38])[CH:36]=[CH2:37])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:37]=[CH:36]/[C:35](=[O:38])[NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:39])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCN(C)CC1)c1ccc(Br)cc1
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCN(C)CC1)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 2-(4-bromo-phenyl)-3-(1-methyl-piperidin-4-yl)-propionic acid methyl ester (2.27 g, 6.67 mmol), (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (2 g, 7.2 mmol), Pd2(dba)3 (160 mg, 0.175 mmol), tri-o-tolylphosphine (160 mg, 0.526 mmol) and triethylamine (1.6 g, 15.8 mmol) in DMF (12 mL) was stirred at 100 degrees Celsius under N2 for 4 hours. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NH4Cl, and extracted with ethyl acetate (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to obtain a pale yellow solid (1.74 g, 50%). MS: calc'd 522 (MH+), exp 522 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4ccccc4)c23)cc1
Yield: 63 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)Quinazoline (1.0 g, 3.7 mmol) and phenyl isocyanate (0.52 g, 4.4 mmol) were reacted in 30 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea (0.9 g, 64.3%, m.p. 231-232° C.).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(C2C3CCC(=O)C=3C=NC=2)=CC=1>>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:2]=[CH:3][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Agent: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)cc1
Product: NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 49 %

Procedure:
In analogy to the procedure described for the preparation of (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 89), replacing 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one with 4-(4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-15). The title compound was obtained as a light brown oil in 49% yield. MS: 279.5 (M+H)+.