Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][CH2:17][C:16]([F:15])([F:29])[F:28])[CH:21]=1
Reactant: O=Cc1cccc(OCCC(F)(F)F)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(CCNCc3cccc(OCCC(F)(F)F)c3)c2c1

Procedure:
Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg 3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4A molecular sieves in 35 mL EtOH and reflux overnight. Decant the liquid into a separate flask and treat with 209 mg (5.5 mmol) NaBH4. Stir the reaction at ambient temperature for 1 hour. Concentrate under vacuum, and partition between 50 mL 1 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 ml dichloromethane and combine the organic layers and concentrate to dryness. Purify the resulting oil by radial chromatography (SiO2; 1% MeOH in CHCl3 mixed with conc. NH4OH) to afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil. Conversion to it's HCl salt by stirring a solution of the compound in 50 mL 50/50 THF/EtOH with 1 g polyvinyl pyridine hydrochloride overnight, filtering and concentrating to a solid. Recrystallize the product from EtOAc: Analysis for C21H23F3N2O2.HCl: calcd: C, 58.81; H, 5.64; N, 6.53. found: C, 58.42; H, 5.44; N, 6.51. ISMS 393 (M+1).
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[C:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[C:8]=3[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.B.FC(F)(F)C(O)=O>C1COCC1>[CH:1]1([NH:4][CH:5]2[CH:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[CH:8]3[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1c2ccc(O)cc2C2CCC(NC3CC3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (8.7 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A 1M solution of borane in THF (540 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back down to 0° C. and trifluoroacetic acid (119 ml) was added in a dropwise manner. The solution was stirred for 15 minutes and THF was removed in vacuo. The mixture was neutralized with 10% NaOH solution, extracted with methylene chloride (4×500 ml), dried (Na2SO4) and concentrated to give 3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (8.8 g).
Reaction SMILES: [F:1]/[CH:2]=[C:3]1/[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]/1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2.C1(=O)CCCCC1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.ClCCl.O>[F:1]/[CH:2]=[C:3]1/[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]/1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C/C(=C/F)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@]12CC/C(=C\F)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 66.6 %

Procedure:
623 mg (E)-3-fluoromethylene-4-androsten-17-beta-ol is dissolved in 25 ml of toluene, mixed with 7 ml of cyclohexanone and three times with 300 mg of aluminum triisopropylate at 160° C. bath temperature on a water separator. After cooling, it is stirred with potassium sodium tartrate for 30 minutes at 60° C., diluted with dichloromethane, washed neutral, dried on sodium sulfate and concentrated. After chromatography on silica gel with hexane/ethyl acetate, 412 mg (E)-3-fluoromethylene-4-androsten-17-one with a melting point of 142°-143° C. is obtained.
Reaction SMILES: O[CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C=CC(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)=CC=1>>[N:41]([CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:42]=[N-:43]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1

Procedure:
Reacting 4-(1-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphonyl azide and diethyl azidocarboxylate gives 4-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this azide with lithium aluminum hydride gives 4-(1-aminotridecyl)-2-triethylsilylfuran. Acetylation of this intermediate with acetic anhydride gives 4-(1-acetamido)tridecyl-2-triethylsilylfuran. Oxidizing this amide with oxygen using Rose Bengal as an initiator gives 4-(1-acetamido)-5-hydroxy-2(5H)-furanone. Reduction of this furanone with sodium borohydride gives 4-(1-acetamido)-2(5H)-furanone.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in a manner analogous to Example 61e. Product isolated as an off-white solid (0.011 g, 13%). MP: 94-115° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 7.97 (s, 1H), 7.94 (s, 1H), 7.33 (br s, 1H), 6.64 (s, 1H), 5.36 (d, 1H, J=7.6 Hz), 5.29 (d, 1H, J=7.1 Hz), 3.99-3.89 (m, 1H), 3.87 (s, 3H), 3.29-3.18 (m, 1H), 2.91-2.80 (m, 10H), 2.79 (s, 3H), 2.27-2.15 (m, 2H), 1.86-1.77 (m, 2H), 1.68 (t, 3H, J=18.8 Hz), 1.40-1.32 (m, 4H). MS: 573 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:37]#[C:36][CH2:35][N:33]([CH3:34])[CH3:32])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CC2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Yield: 70 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.070 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and N,N-dimethylpropargylamine (0.020 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H20. The aqueous layer is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. Recrystallization with CH2Cl2/hexanes affords the desired product (0.046 g, 70%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: NCc1cccnc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCc4cccnc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-pyridin-3-ylmethyl-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 3-(aminomethyl)-pyridine (0.82 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (163 mg, 53%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64 (d, J=6.5 Hz, 1H), 8.62 (s, 1H), 8.44 (m, 1H), 8.38 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.47 (t, J=12.8, 6.4 Hz, 1H), 7.35 (m, 1H), 7.04 (t, J=14.2, 7.2 Hz, 1H), 4.50 (d, J=6.2 Hz, 2H), 3.28 (s, 3H). MS=380 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[CH:2].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[N+:25]=[N-:26]>C(O)(C)(C)C.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([C:1]2[N:26]=[N:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=3)[CH:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cccc(-c2cn(-c3ccc(C(=O)O)cc3)nn2)c1
Reaction time: 168 h
Yield: 99.3 %

Procedure:
To a solution of 1-ethynyl-3-methoxybenzene (396 mg, 3.00 mmol, Aldrich) in 50% tert-butanol/water (4.0 mL) is added 300 μL (0.30 mmol) of an aqueous solution of sodium ascorbate (594 mg in 3 mL H2O), 100 μL (0.030 mmol) of an aqueous CuSO4.5H2O solution (75 mg in 1 mL H2O), followed by 4-azidobenzoic acid (489 mg, 3 mmol). The resulting mixture is stirred for 7 days, the resulting suspension filtered and washed with H2O (3×30 mL), Et2O (2×15 mL), and hexanes (3×30 mL). The solid is dried overnite in vacuo (70° C., 10 torr) to afford 880 mg (99%) of 4-[4-(3-methoxy-phenyl)-[1,2,3]triazol-1-yl]benzoic acid as a pale yellow powder: m.p. 276-277° C. 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.16 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 7.52 (m, 2H), 7.40 (t, J=7.8 Hz, 1H), 6.95 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 3.82 (s, 3H). MS m/z 296.29, calcd for C16H13N3O3 (M+H+) 296.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27](=[O:36])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:34][CH:33]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)cc1
Yield: 49 %

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate (3.25 g, 10 mmol) and tert-butyl(4-aminophenyl)carbamate (2.08 g, 10 mmol) were used in a process similar to Example 1(1) to give the titled compound as a red solid (1.88 g, yield 49%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:13]=[C:12]([C:14](OCC)=[O:15])[C:11](=S)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]2=3)=[CH:3][CH:2]=1.Cl.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][NH2:38].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:13]=[C:12]3[C:14](=[O:15])[N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[F:30])[N:38]=[C:11]3[C:10]3[CH2:20][CH2:21][CH2:22][C:9]2=3)=[CH:5][CH:6]=1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=S)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3c(c-2nn1-c1ccccc1F)CCC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (0.30 g, 0.77 mmol) was suspended in ethanol (10 mL) and treated with 2-fluorophenylhydrazine hydrochloride (0.38 g, 2.3 mmol, 3 equiv) and potassium carbonate (0.64 g, 4.6 mmol, 6 equiv). The mixture was placed into a preheated oil bath at 80° C. for 24 hours, cooled to ambient temperature and concentrated in vacuo. The residue was treated with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.29 (1H, s), 7.61-7.56 (5H, m), 7.47-7.44 (2H, m), 7.40-7.30 (2H, m), 7.21-7.19 (2H, m), 5.20 (2H, s), 3.08 (2H, t, J=7.5 Hz), 2.94 (2H, t, J=7.5 Hz), 2.23 (2H, quin, J=7.5 Hz) ppm; low resolution mass spectrometry (ES+) m/z 436.1 [(M+H)+; calculated for C28H23FN3O: 436.2].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:84]1[CH2:89][CH2:88][O:87][CH2:86][CH2:85]1>CN(C=O)C.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:84]3[CH2:89][CH2:88][O:87][CH2:86][CH2:85]3)=[C:3]([F:28])[CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Br)c(F)c2)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(N3CCOCC3)c(F)c2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide 0.2 g (0.4 mmol), potassium phosphate tribasic monohydrate 0.570 g (2.4 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.077 g (0.12 mmol), morpholine 0.17 g (2 mmol) and Pd (dba)3 0.057 g (0.06 mmol) in 2 ml DMF. HPLC purification gave a yellow compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20]([OH:22])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20](=[O:22])[NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:36])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NCCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid 1-benzyl ester was coupled with β-alanine benzyl ester to give 3-[[2-[(benzyloxy)carbonyl]ethyl]carbamoyl]-N-(t-butoxycarbonyl)-L-alanine benzyl ester, m.p. 77°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1
Agent: O=C1CNCCN1
Product: Cc1cc(-n2nc(C(=O)N3CCNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
50 mg (0.11 mmol) of the compound of Example 48A is reacted analogously to the synthesis of the compound of Example 1 with 12 mg (0.12 mmol) of 2-oxopiperazine. 51 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>CN(C=O)C.C(OCC)C>[CH2:19]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[O:9][CH:10]([CH3:12])[CH3:11])[CH3:20]
Reactant: CCI
Reactant: CC(C)Oc1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(I)ccc1OC(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 5-iodo-2-isopropoxyphenol (2.3 g, 8.3 mmol) in DMF (20 mL), K2CO3 (2.3 g, 16.5 mmol) and ethyl iodide (0.86 mL, 10.8 mmol) were added. The mixture was stirred at 40° C. for 2.0 h. It was diluted with diethyl ether, washed with brine, dried over MgSO4. The crude was purified by chromatography (5:1 EtOAc/hexanes) to give 2-ethoxy-4-iodo-1-isopropoxybenzene (2.5 g, 96% yield) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[NH:9][C:8](=O)[C:7]=2[N:21]=1.O=P(Cl)(Cl)[Cl:24].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:7]2[N:21]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=2[N:9]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nc(SC)ncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
methyl 3-(methylthio)-5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 279 mg, 0.926 mmol) was suspended in toluene (2 ml). POCl3 (2 ml) and DIEA (0.5 ml) were added and the mixture stirred at 120° C. for 5 hours. The volatiles were removed in vacuo and CH2Cl2 was added. The organic phase was washed with saturated aqueous sodium bicarbonate, washed with water and dried over Na2SO4. The solution was filtered through a pad of celite and the solvents removed in vacuo. The material was triturated in hexanes and AcOEt, filtered and dried to provide methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate as a beige solid (184 mg, 63% yield). LCMS (ES): >95% pure, m/z 320 [M+1]+, 322 [M+3]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cc2c(nn1)CCCCCC2
Solvent: O
Product: NNc1cc2c(nn1)CCCCCC2

Procedure:
11.7 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 60 cc of hydrazine hydrate are reacted in accordance with the process described in Example 1. The orange-coloured solution is completely concentrated, and the remaining crystalline crude title compound is washed with water. M.P. 145°-145° (decomp., from absolute ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CC3)c(=O)n12
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0,088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 5.025 g (0.088 mol) of cyclopropylamine in 80 ml of chloroform are dropped to the above solution at the same temperature during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 14.5 g (74.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CC(C)CC(=N)NO
Product: CC(C)Cc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-3-methyl-butyramidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.76 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[NH:33][CH2:32][CH2:30][OH:31])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2NCCO)cn1)c1ccc(Cl)s1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (75 mg, 0.17 mmol) and ethanolamine (1.5 mL) in DMSO (1 mL) in a sealed tube was heated at 150° C. overnight. The mixture was purified by HPLC to give the title compound (13 mg). MS 470.0 and 472.0 (M+H, Cl pattern).