Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][CH2:44][C:45]([OH:47])([CH3:48])[CH3:46])=[CH:38][C:37]=2[CH3:49])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(CCC(C)(C)O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenyl)-2-methylbutan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.83 min; Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20](N)[CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CCCCO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH3:21])=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc([C@H](C)N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc([C@H](C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 160 °C
Yield: 64.6 %

Procedure:
To phthalimide (1.3 g, 0.0088 mol) in a 2-5 mL microwave vial was added (S)-1-(4-methoxyphenyl)ethan-1-amine (2.20 mL, 0.015 mol) and K2CO3 (1.2 g, 0.0087 mol). The reaction mixture capped and heated at 160° C. for 2 minutes. The resulting crude solid was suspended in n-BuOH and was filtered. The filtrate was put aside. The solid was washed with H2O and the filtrate was discarded. The solid was washed with CH2Cl2 and the resulting filtrate was partitioned with H2O. The organics (n-BuOH and CH2Cl2 layer) were combined and concentrated. The crude residue was purified by silica gel column chromatography using CH2Cl2 as eluent to yield 1.6 g (64%) of the title compound. LC/MS: m/z (ES+) 282 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[C:13]3[C:14](=[O:28])[N:15](CC4C=CC(OC)=CC=4OC)[CH2:16][C:12]=3[C:11]([F:29])=[C:10]([NH:30][C@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33])[N:9]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)(C(F)(F)F)=O>[C:1]([C:3]1[S:7][C:6]([C:8]2[C:13]3[C:14](=[O:28])[NH:15][CH2:16][C:12]=3[C:11]([F:29])=[C:10]([NH:30][C@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33])[N:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccc(C#N)s4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](Nc1nc(-c2ccc(C#N)s2)c2c(c1F)CNC2=O)C(N)=O
Yield: 17 %

Procedure:
A solution of (R)-2-(4-(5-cyanothiophen-2-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (68 mg, 0.126 mmol) in TFA (2 mL) was heated to 65° C. for 3 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DCM (3.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40%, 0.035% TFA). The collected fractions were combined and the solvent was removed via rotary evaporation to yield the title compound (8.3 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86-0.96 (m, 6 H), 1.53-1.62 (m, 1 H), 1.67-1.88 (m, 2 H), 4.45 (s, 2 H), 4.50-4.57 (m, 1 H), 6.96-7.06 (m, 1 H), 7.32-7.54 (m, 2 H), 7.86-8.02 (m, 1 H), 8.61 (s, 1 H), 9.00-9.15 (m, 1 H). [M+H] calc'd for C18H18FN5O2S, 388; found, 388.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:14][CH2:15]Br)[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:12][CH3:13]
Reactant: CCCOCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOCOc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrophenol, bromomethyl propyl ether, anhydrous potassium carbonate and acetone were reacted according to the procedure outlined in Example 1 to yield 2-propoxymethoxynitrobenzene, which was reduced to the corresponding aniline, and isolated by a vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:13][N:12]=[C:11]([NH:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=2)[N:10]=1.NN>C(O)C>[NH2:15][C:14]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[N:10][C:11]([NH:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=2)=[N:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Product: Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]isoindoline-1,3-dione and 20 mmol of hydrazine were stirred in ethanol at 75° C. for two hours and then purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26].CN1CCOCC1>CO>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CC(=O)NCCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(=O)NCCNS(=O)(=O)c1ccc2nc(-c3c(C)n[nH]c3N)sc2c1
Yield: 43.9 %

Procedure:
the title compound (52 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N-(2-aminoethyl)-acetamide (58 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.6 (M+1, 100%). Yield=43%.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([OH:28])=O.[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH2:40])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][C:26](=[O:28])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(C(C)(C)C)cc(N)n1
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)n1
Yield: 21.9 %

Procedure:
Combine [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (0.66 g, 1.57 mmol), 4-tert-butyl-6-methyl-pyridin-2-yl-amine (0.26 g, 1.57 mmol), HATU (0.72 g, 1.57 mmol), diisopropylethylamine (8.12 g, 11.2 mL, 6.28 mmol) in DMF (10 mL) and stir at ambient temperature for 3 hours. Pour the reaction contents onto a pre-washed (with methanol) Varian SCX column (25 g) and wash the column with portions (30 mL) of dichloromethane (2×) and methanol (3×). Elute the product with 2N methanolic ammonia (75 mL) and concentrate the solution to dryness. Chromatograph the crude product on silica using (0-5%) methanol in dichloromethane. Recrystallization from dichloromethane/ether/hexanes provides N-(4-tert-Butyl-6-methyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide (0.17 g). MS(ES), m/z 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]2)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 556.9 [M+H]+; single peak at tR=3.36 min (System 1); Rf=0.13 (CH2Cl2/MeOH+1% NH33aq, 9:1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)=[CH:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C:15]3[CH2:16][CH2:17][CH:12]([N:10]4[CH2:11][CH:8]([NH2:7])[CH2:9]4)[CH2:13][CH:14]=3)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
A solution of [1-(4-Benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-yl]-carbamic acid tert-butyl ester (as prepared in the previous step, 750 mg, 2.02 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=O)[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[NH2:33][OH:34]>C(O)C>[CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[N:33][OH:34])[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: NO
Reactant: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)s2)CC1
Solvent: CCO
Product: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)s2)CC1
Yield: 22 %

Procedure:
The product of step 4 (300 mg, 0.8 mmol) was heated at reflux in ethanol (10 ml) containing hydroxylamine (50% aqueous solution) (1 ml) for 1 hour. The solution was co-evaporated in ethanol (×3) to afford a crude solid. The product was purified twice by silica gel chromatography (1:9:40 0.880 ammonia:thanol:dichloromethane) to afford the title compound (80 mg, 22%); MS (AP+) m/e 461 [M+H]+
Reaction SMILES: BrC1C=C2C(C(N[C@H]3CCN(C(OC(C)(C)C)=O)C3)=N[C:8]([C:12]3C=CC=C[C:13]=3[OH:18])=N2)=CC=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[N:48]=[C:47]([NH:49][C@H:50]2[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51]2)[C:46]2[C:41](=[CH:42][CH:43]=[C:44](C#CCO)[CH:45]=2)[N:40]=1>>[OH:18][CH2:13][CH2:12][CH2:8][C:43]1[CH:42]=[C:41]2[C:46]([C:47]([NH:49][C@H:50]3[CH2:54][CH2:53][NH:52][CH2:51]3)=[N:48][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[OH:32])=[N:40]2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1
Product: OCCCc1ccc2c(N[C@H]3CCNC3)nc(-c3ccccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[C:20]([CH2:22][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:19]2[O:18][C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[N:21][C:20]=2[CH2:22][O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(Cl)cc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccc(Cl)cc1

Procedure:
A solution of 4-[5-(4-Chlorophenyl)-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (3.7600 g, 7.3880 mmol) in trifluoroacetic acid (10 mL, 130 mmol) was stirred at RT for 3 d, then concentrated to a thick oil. This is dissolved with heating in a mixture of hexane and diethyl ether which, upon cooling, precipitated cream-colored solids. These are collected, washed with hexane and dried in vacuo at RT. Reworking the mother liquors gives a second crop of solids. The crops are combined to give the title compound as cream colored solids.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:5](Cl)[N:4]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:5]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:4]=1
Reactant: CCCCc1c(Cl)cc(CO)nc1Cl
Reactant: C1CCNCC1
Product: CCCCc1c(Cl)cc(CO)nc1N1CCCCC1

Procedure:
46.8 g (0.2 mol) of 2-hydroxymethyl-4,6-dichloro-5-n-butyl-pyridine dissolved in 425 g (5 mols) of piperidine are heated for 20 hours at 190° in a bomb tube. The reaction mixture is then evaporated and the piperidine which still adheres is distilled off by means of toluene. The residue is rendered alkaline with 2 N sodium carbonate solution and the mixture is extracted with ether. The ether phases are combined, dried over sodium sulphate, filtered and evaporated. Fractional distillation of the residue in a high vacuum yields 2-hydroxymethyl-4-chloro-5-n-butyl-6-piperidino-pyridine of the formula ##STR17## and of boiling point 147°-152° (0.25 mm Hg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16]O)[CH:5]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][C:25]=1[CH3:31])[CH3:19].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C.O>[CH2:18]([O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:16][C:4]2[CH:5]=[C:6]([O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:26][C:25]=1[CH3:31])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CO)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1ccc(SCc2cc(Br)cc(O[Si](C)(C)C(C)(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol (6.4 g; 20.17 mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (5.02 g; 22.19 mmol) were dissolved in THF (200 mL). Tributylphosphine (8.15 g; 40.34 mmol) and 1,1′-(azodicarbonyl)dipiperidine (10.17 g; 40.34 mmol) were added, and the reaction mixture was stirred for 14 h at room temperature. Water and ethyl acetate were added to the reaction mixture. The phases were separated. The organic phase was washed with water, dried, and evaporated. The crude product was purified by flash chromatography (heptane:dichloromethane (1:1)). Yield: 8 g; 80%. HPLC-MS: m/z: 527.0 (M+1); Rt: 3.10 min.
Reaction SMILES: [CH3:1][N:2]([CH3:11])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1>N1CCCCC1>[CH3:11][N:2]([CH3:1])[C:3]1[CH2:4][CH2:5][C:6]2[C:10]=1[CH:9]=[CH:8][CH:7]=2
Reactant: CN(C)/C=C/C=C1C=CC=C1
Solvent: C1CCNCC1
Product: CN(C)C1=C2C=CC=C2CC1

Procedure:
A solution of 20.0 g (136 mmol) of (E)-6-[2-(dimethylamino)ethenyl]-fulvene in 100 ml of piperidine is boiled under reflux for 2 hours. The solvent is removed under reduced pressure and the residue is recrystallized from diethyl ether. This gives 12.5 g (63%) of 4-(dimethylamino)-5,6-dihydropentalene in the form of a yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:21])([CH3:20])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:5].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:2][C:3]1([CH3:21])[CH2:20][N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[C:4]1=[O:5]
Reactant: CC(C)(CCl)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1=O
Temperature: 50 °C

Procedure:
To a mixture of 3-chloro-2,2-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)propanamide (3.24 g, 10.0 mmol, 1.0 equiv) in acetone (100 mL) was added K2CO3 (3.5 g, 25.0 mmol, 2.5 equiv). was heated to 50° C. for 48 h. After filtering, the solvent was removed in vacuo and the resulting residue purified by silica gel chromatography (1:10 hexanes:EtOAc to 1:5 hexanes:EtOAc) to afford lactam 3. MS (MH+) 289.1; Calculated 289.1 for C12H12F3N2O3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:20])=[O:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
To a solution of 5-benzyloxypyridine-2-carbaldehyde (3.8 g) in acetone (50 ml) was added water (50 ml), sulfamic acid (2.4 g) and sodium chlorite (2.2 g) were sequentially added thereto on an ice bath, and the solution was stirred for 6 hours at room temperature. The solid that was precipitated was filtered and rinsed with water to provide the title compound (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][NH:20][C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32]=O>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:32])[C:21]4([C:26]([OH:28])=[O:27])[CH2:22][CH:23]=[CH:24][CH2:25]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC=CC1
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CC=CC1

Procedure:
1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopent-3-ene-1-carboxylic acid was methylated by reaction with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopent-3-ene-1-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 2.21 (s, 3H); 2.62 (d, 2H); 2.99 (d, 2H); 3.73 (s, 2H); 3.95 (s, 3H); 5.71 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.52 (m, 2H); 8.34 (s, 1H); 8.42 (s, 1H); 9.77 (s, 1H); Mass Spectrum: (M+H)+ 457.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CCCC)CCCC)CCC>[NH2:1][C:2]1[N:6]=[C:5]2[N:7]=[C:15]([OH:16])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:20]([OH:21])[N:4]2[N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1n[nH]c(N)n1
Solvent: CCCCN(CCCC)CCCC
Product: Nc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Temperature: 25 °C

Procedure:
A solution of 9.0 g 3,5-diamino-1,2,4-triazole and 22.4 ml diethyl phenylmalonate in N,N-dibutylbutan-1-amine is heated under microwave irradiation to 180° C. for 8 h. The reaction mixture forms two layers after cooling to room temperature. The top layer is removed and the solvent of the lower layer is evaporated. The residue is treated with water and acidified with 5N HCl. The precipitated product is collected by filtration and dried. The crude product is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH2:19][CH2:20][C:21]1[N:25]2[C:26]3[S:40][C:39]([CH2:41][CH3:42])=[CH:38][C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[C:27]2[CH:38]=[C:39]([CH2:41][CH3:42])[S:40][C:26]=2[N:25]2[C:21]([CH2:20][NH:19][C:16]([C:8]3[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:18])=[N:22][N:23]=[C:24]2[CH2:30][N:29]=1
Reactant: CCOC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc3n2-c2sc(CC)cc2C(c2ccccc2Cl)=NC3)cc2ccccc21
Reaction time: 24 h
Yield: 60.3 %

Procedure:
1-Ethoxycarbonylmethylindole-2-carboxylic acid (1.36 g) synthesized by a known method such as the method described in Japanese Patent Unexamined Publication No. 279374/1991, 9-aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.79 g) and triethylamine (1.4 ml) were dissolved in dimethylformamide (15 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 2.43 g) was added at room temperature, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol and isopropyl ether to give 2.78 g of crude crystals. The crystals were recrystallized from ethanol to give 1.77 g of ethyl 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethylcarbamoyl)indole-1-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=2)[CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1nc(N2CCCC2)nc1C=Cc1nc2ccc(Cl)cn2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1nc(N2CCCC2)nc1CCc1nc2ccc(Cl)cn2n1
Reaction time: 2 h
Yield: 15.3 %

Procedure:
A suspension of 6-chloro-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyridine (50 mg, 152 μmol, Eq: 1.00) and 5% Pd on Ba2SO4 (150 mg) in EtOAc (5 ml) was stirred under hydrogen (1 atm) for 2 h. The mixture was filtered over Celite and the residue purified by prep. HPLC to give the desired product (7.7 mg, 15%) as a white solid. MS: m/z=331.9 (M+H+)