Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH3-]C#N.[Na+].[OH-].[Na+].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1>C(O)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:36][CH2:35][N:34]([CH2:50][C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)[CH2:33][CH:32]=3)=[CH:27][CH:26]=2)(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCN(Cc3cccnc3)CC2)cc1

Procedure:
A mixture of Example 340A (65 mg, 0.1 mmol), NaBH3CN (48 mg, 0.75 mmol), 2N NaOH (0.15 mL), and 3-pyridinecarboxaldehyde (214 mg, 2 mmol) in acetic acid (0.5 mL) and methanol (1 mL) was stirred for 16 hours. The reaction mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC using 20-90% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(−)) m/e 628 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (br t, 1H), 8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d, 2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Methyl 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)-carbamoyl)-4,5-dihydrobenzo[b] thieno[2,3-d]oxepine-8-carboxylate (25.00 g, 50.1 mmol) was dissolved in THF (50 mL) and water (50 mL). The solution was treated with LiOH.H2O (5.26 g, 125.3 mmol). The reaction mixture was stirred at room temperature for 2 h. Concentrated to remove the solvent THF and the mixture was acidified by 2N HCl. The resulting precipitate was filtrated, washed by water, dried to give 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (20.00 g, 82%). ESI-MS: 485.1. 1H NMR (CDCl3, 400 MHz): δ7.66-7.60 (m, 3H, ArH), 7.46-7.42 (m, 3H, ArH), 6.99 (s, 1H, ═CH), 4.23 (t, J=5.0 Hz, 2H, CH2), 3.39 (s, 3H, CH3), 3.14 (s, 3H, CH3), 3.07 (t, J=5.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:11])=[O:10]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
1-(4-Bromo-2-fluorophenyl)ethanone (2.59 g, 11.9 mmol, 1.00 equiv) was dissolved in chloroform (5 mL) and cooled to 5° C. Bromine (0.613 mL, 11.9 mmol, 1.00 equiv) was added dropwise via syringe. On completion of the addition, the bath was removed and the reaction was allowed to warm to room temperature. After two hours, the reaction was poured onto ice and diluted with EtOAc. The mixture was washed sequentially with saturated NaHCO3, water, and saturated NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to afford 3.14 g (89%) of a white solid. 1H NMR (CDCl3) 7.92-7.83 (m, 1H), 7.51-40 (m, 2H), 4.50 (s, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C@@H:8]([CH2:20][O:21][Si:22]([CH3:28])([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:7]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+].[I:44]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:27][Si:22]([CH3:28])([C:23]([CH3:24])([CH3:26])[CH3:25])[O:21][CH2:20][C@H:8]1[C@H:7]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:6][C@@H:5]([OH:4])[C@@H:9]1[CH2:10][CH:11]([C@H:12]1[O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13]1)[I:44]
Reactant: II
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](CC(I)[C@@H]2CCCC(=O)O2)[C@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a tetrahydrofuran (140 mL) solution of the compound 4 (34.9 g) was added a 2M aqueous sodium hydroxide solution (140 mL), and the mixture was stirred at room temperature for 18 hours and then at 50° C. for 3 hours. The mixture was cooled to −4° C. in an ice-methanol bath, and to the reaction mixture was then added dropwise 2 M hydrochloric acid (111 mL) over 12 minutes while the mixture was kept at 2° C. or lower (pH 5 to 6). The cooling bath was changed to an ice bath, and to the reaction mixture were added sodium hydrogen carbonate (28.5 g) and iodine (17.5 g), and the mixture was stirred. After 2 hours, iodine (34.2 g) was added, the mixture was further stirred for 2.5 hours, and a 5% aqueous sodium thiosulfate solution (1380 mL) was then added. When the color of iodine mostly disappeared, ethyl acetate (600 mL) was added, the mixture was stirred, and the two layers were separated. The organic layer was washed with water (150 mL) and a saturated saline (150 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→5:6) to obtain titled compounds having the following physical property values (low polar compound 8.0 g; high polar compound 20.8 g).
Reaction SMILES: [C:1]1([NH:13][CH:14]=[C:15]([C:21]([O:23]CC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]CC=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:23][C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCCCCCC1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 46.0 g of diethyl N-(1-cyclododecenyl)aminomethylenemalonate in 40 ml of Dowtherm® is added to one liter of Dowtherm® at 250° under argon, and the distillate is collected in a Dean-Stark trap. After 0.5 hour the mixture is allowed to cool to room temperature and the solvent is distilled off. The residual solid is triturated with ether to give ethyl 4-hydroxy-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate, m.p. 212°-30°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16])[CH3:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C=O
Temperature: 110 °C
Yield: 35.4 %

Procedure:
5-Fluoro-2-hydroxy-benzaldehyde (14 g, 100 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (19.5 g, 100 mmol), K2CO3 (27 g, 196 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (150 mL). Then the reaction mixture was heated at 110° C. for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with aqueous 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (9 g).
Reaction SMILES: O[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH2:8]([O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][C@@H:24]([O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([N:51]3[CH2:57][CH2:56][C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[NH:53][C:52]3=[O:62])[CH2:47][CH2:46]2)=[O:44])[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[O:26])=[CH:18][C:17]=1[CH3:63])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:8]([O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][C@@H:24]([O:42][C:43]([N:45]2[CH2:46][CH2:47][CH:48]([N:51]3[CH2:57][CH2:56][C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[NH:53][C:52]3=[O:62])[CH2:49][CH2:50]2)=[O:44])[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:34][CH2:35][CH:36]([C:39]([O:41][CH2:2][C:3](=[O:4])[N:5]([CH3:7])[CH3:6])=[O:40])[CH2:37][CH2:38]3)[CH2:29][CH2:28]2)=[O:26])=[CH:18][C:17]=1[CH3:63])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)CO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)O)CC3)CC2)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30 mg (0.29 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added at RT to a solution of 200 mg (0.25 mmol) 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylic acid (Example 6.1a), 90 mg (0.28 mmol) TBTU and 80 μL (3.73 mmol) triethylamine in 1.8 mL DMF and this was stirred for 20 h at RT. The reaction mixture was poured onto saturated NaHCO3 solution, the precipitate formed was suction filtered and dried. Further purification was carried out by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCOc1ccc2c(c1)c(CC(=O)OC)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (0.35 g), ethyl 5-bromopentanoate (0.232 ml) and potassium carbonate (0.31 g) in methylethylketone (5 ml) was stirred at 80° C. for 18 hours. After an insoluble mass was filtered off, the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and n-hexane. The fractions containing the objective compound were combined and concentrated under reduced pressure. The residue was crystallized with n-hexane and the crystals were collected by filtration and washed with n-hexane to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-methyl}-5-(4-ethoxycarbonylbutoxy)indole-3-acetate (0.23 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1>C1COCC1>[NH2:9][C:10]1[N:15]=[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:13]=[C:12]([C:17]([F:20])([F:18])[F:19])[N:11]=1
Reactant: OCC(F)(F)F
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
2,2,2-Trifluoroethanol (2.2 mL, 30 mmol) was slowly added to a suspension of NaH (1.5 g, 36 mmol, 60% dispersion in mineral oil) in anhydrous THF (50 mL) under an N2 atmosphere. To the resulting mixture was added a solution of 2-amino-4-chloro-6-trifluoromethylpyrimidine (5.0 g, 25 mmol; for preparation see: Giner-Sorolla, A. and Bendich, A. J. Am. Chem. Soc. 1957, 80, 5744 and Gershon, H. et al. J. Het. Chem. 1983, 20, 219) in anhydrous THF (50 mL). The resulting mixture was stirred 18 h at room temperature and the solvent evaporated. The resulting residue was partitioned between CH2Cl2 (200 mL) and H2O (200 mL). The organics separated, dried over MgSO4, filtered and evaporated to afford 2-amino-4-(2,2,2-trifluoroethoxy)-6-trifluoromethyl-pyrimidine as a tan solid (4.9 g, 74% yield): m.p. 108-110° C.; 1H NMR (CDCl3) δ 6.54 (s, 1H), 5.53 (bs, 2H), 4.76 (q, 2H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 261 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: COC(=O)c1cccc(N)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylumnium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 m L) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21](=[O:43])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:38]=[CH:37][C:36]4[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=4[CH:30]=3)[N:24]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:39][C:35]1([CH3:40])[CH2:34][CH2:33][C:32]([CH3:41])([CH3:42])[C:31]2[CH:30]=[C:29]([C:25]3[N:24]=[C:23]([NH:22][C:21]([CH:17]4[O:18][CH2:19][CH2:20][NH:15][CH2:16]4)=[O:43])[CH:28]=[CH:27][CH:26]=3)[CH:38]=[CH:37][C:36]1=2
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(NC(=O)C4CNCCO4)n3)ccc21

Procedure:
The protecting group is cleaved off as already described using TFA in DCM starting from 92 mg (0.19 mmol) of 2-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-ylcarbamoyl]morpholine-4-carboxylic acid tert-butyl ester from step b. The product is purified by means of preparative HPLC and is in the form of the TFA salt.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][N:26]=3)[C:23]=2[OH:24])=[CH:15][CH:14]=1)#[N:12].[C:34]([NH2:38])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.CS(C)=O.C(Cl)CCl>[C:34]([NH:38][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([N:22]2[C:23]([OH:24])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=3)[CH:20]=[N:21]2)=[N:26][CH:27]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Reaction time: 4 h
Yield: 16.7 %

Procedure:
Combined EDC (45.1 mg, 0.235 mmol), HOBT (21.18 mg, 0.157 mmol) and 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (48 mg, 0.157 mmol) in DMF (1 mL) then added tert-butylamine (0.050 mL, 0.470 mmol) and Hunig's base (0.082 mL, 0.470 mmol) and then stirred at 20° C. for 21 h. Addition EDC (45 mg) and tert-butyl amine (100 uL) were then added and stirring continued at 20° C. for 4 h. Then additional HATU (119 mg, 0.313 mmol) was added and stirring continued at 20° C. for 2 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate, and concentrated in vacuo to give a residue which was dissolved in DMSO (1 mL) and purified by prep HPLC (ACN/water with formic acid) to give the title compound (9.5 mg, 16.77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 7.72 (d, J=8.3 Hz, 2H) 7.98 (s, 1H) 8.07 (br. s., 2H) 8.33 (d, J=7.3 Hz, 2H) 8.58 (br. s., 1H) 8.79 (s, 1H) 13.48 (br. s., 1H). MS m/z 362 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11](Br)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c2[nH]c(N3CCCCC3)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-bromo xanthine (2 g, 0.0029 mol) was dissolved in toluene (50 ml). After addition of piperidine (5 g, 0.0058 mol) the mixture was refluxed for 9 hours. The reaction mixture was then extracted with water (4×30 ml), the organic layer dried over anhydrous sodium sulphate and the solvent removed in vacuo. The residue was recrystallised from ethanol to give the title product, yield 0.4 g (20%), m.pt. 221° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30](F)[C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:29].[CH3:35][S:36](C)=O>O>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([S:36][CH3:35])[C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:29]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(Cc5c(F)cccc5F)c4n3)cc2)CC1
Reactant: CS(C)=O
Solvent: O
Product: CSc1cccc(F)c1Cn1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 90 %

Procedure:
8-(2,6-difluorobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (23 mg, 0.05 mmol, Example 61) was treated with NaSMe (5 mg, 0.06 mmol) in DMSO (0.2 mL) at 100° C. for 2 h. The reaction mixture was diluted with water, the precipitated product was filtered off, then purified by silica gel column chromatography using dichloromethane:methanol (95:5) to give 8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (22 mg, Y=90%). ESMS m/z 491 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[NH:9][N:8]=1.S([O-])(O)=O.[Na+]>CN(C)C=O>[Br:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Agent: Cl[Sn]Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]nc(Br)c2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
Tin dichloride dihydrate (846 mg, 3.75 mmol) was added to a solution of 3-bromo-5-nitro-1H-indazole (181 mg, 0.748 mmol) in N,N-dimethylformamide (3 ml), and the resulting mixture was stirred at 70° C. for 1.5 hours. After an aqueous sodium hydrogensulfite solution was added thereto to terminate the reaction, ethyl acetate was added to the reaction mixture and the insoluble material was removed by filtration using Celite. The residue was extracted with ethyl acetate/toluene, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 3-bromo-1H-indazol-5-amine (110 mg, 69%) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([C:33]3[CH:43]=[CH:42][C:36]([C:37](OCC)=[O:38])=[CH:35][CH:34]=3)[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.CO.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:2]([O:9][NH:10][C:37](=[O:38])[C:36]1[CH:42]=[CH:43][C:33]([C:24]2[NH:25][C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[N:23]=2)=[CH:34][CH:35]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: NOCc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NOCc1ccccc1)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a stirred suspension of O-benzyl-hydroxylamine hydrochloride (1.2 g, 7.8 mmol) in toluene (20 mL) at 0° C. was added trimethylaluminum (2.0 M in toluene, 3.9 mL, 7.8 mmol). The reaction mixture was warmed to rt and stirring was continued at this temperature for 1 h. Ethyl 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoate (1.0 g, 2.6 mmol) [See Ex. 14 above] was added and the reaction mixture was heated at reflux for 3 h. After cooling, the reaction was poured into 10% MeOH/CHCl3 containing silica gel. The solids were removed by filtration and washed with 10% MeOH/CHCl3. The combined washings were evaporated and the residue was purified by flash chromatography eluting with a solvent gradient of 1-10% MeOH/CHCl3. Trituration with ether afforded the title compound as a white solid (0.25 g, 21%): 1H NMR (CDCl3/MeOH-d4): d 8.16 (d, 2H); 7.77 (d, 2H); 7.53 (d, 2H); 7.23 (m, 5H); 7.10 (m, 4H); 6.88 (t, 2H).