Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]=O)[CH2:12][CH2:11]1)=[O:8].[CH2:20]([C:22]1[NH:26][N:25]=[C:24]([NH2:27])[C:23]=1[CH3:28])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][NH:27][C:24]2[C:23]([CH3:28])=[C:22]([CH2:20][CH3:21])[NH:26][N:25]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCc1[nH]nc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1[nH]nc(NC[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising trans-5-chloro-N-(4-formyl-cyclohexyl)-2-methyl-nicotinamide Intermediate E) (100 mg, 0.30 mmol) and 5-ethyl-4-methyl-1H-pyrazol-3-amine (37.5 mg, 0.30 mmol) in DCM (5 ml) was treated with sodium triacetoxyborohydride (95 mg, 0.45 mmol). The reaction mixture was stirred at RT for 18 hours and then partitioned between DCM and sat. NaHCO3. The organic phase was passed through a phase separator and the solvent was removed in vacuo. The resulting crude product was triturated in EtOAc, filtered and dried to afford the title compound; 1H NMR (d6-DMSO, 400 MHz) δ 10.87 (1H, s), 8.53 (1H, m), 8.40 (1H, m), 7.80 (1H, m), 4.43 (1H, m), 3.69 (1H, m), 2.90 (2H, t), 2.50 (3H, s), 2.40 (2H, q), 1.88 (4H, m), 1.73 (3H, s), 1.53 (1H, m), 1.21 (2H, m), 1.09 (3H, t), 1.00 (2H, m); LCMS Rt=2.06 min, [M+H]+390 Method LowpH_v002.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([OH:38])=[CH:33][CH:34]=[C:35]([F:37])[CH:36]=2)[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[C@@H:40]([CH3:42])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C@@H:40]([CH3:42])[C:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (0.19 ml) was added to a solution of the product of example 2 part (iii) (250 mg), tert-butyl (R)-(+)-lactate (141 mg) and triphenylphosphine (252 mg) in tetrahydrofuran (10 ml) at 0° C. After 20 minutes the ice bath was removed and the reaction stirred at room temperature overnight. The reaction mixture was then adsorbed onto silica and purified using flash column chromatography (eluent 10% ethylacetate/hexane) to give the subtitle compound as an oil, yield 140 mg.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([Cl:14])=[CH:23][C:22]=3[Cl:24])[CH2:18][CH2:19]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Product: CSCCn1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 127-128° C.; 1H NMR (300 MHz, CDCl3): δ 7.19 (d, J=1.8 Hz, 1 H), 7.12 (d, J=2.2 Hz, 1 H), 6.93 (s, 1H), 4.36 (t, J=8.1 Hz, 2 H), 4.06 (t, J=7.0 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 2.89 (t, J=7.0 Hz, 2 H), 2.16 (s, 3 H); HRMS (CI) calcd for C15H14N3OSCl3 (M+) 388.9923; found m/z 388.9920.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.N(CC)CC.[Cu]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>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCSc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) CuI in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]([CH2:5][C:6]([OH:8])=[O:7])[NH2:4].[C:10](Cl)(=[O:12])[CH3:11].Cl>[OH-].[Na+].O1CCOCC1>[F:1][CH:2]([F:9])[CH:3]([NH:4][C:10](=[O:12])[CH3:11])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)Cl
Reactant: NC(CC(=O)O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)NC(CC(=O)O)C(F)F

Procedure:
To a solution of 2 mmole of beta-difluoromethyl beta-alanine in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 160 mg of acetyl chloride diluted in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 3-difluoromethyl-3-(1-oxo-ethylamino) propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)Cl>CC#N>[CH3:1][O:2][C:3]1[CH:19]=[C:18]2[C:6]([CH2:7][CH2:8][N:9]=[C:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCNC(=O)c2ccccc2)cc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC2
Yield: 661.6 %

Procedure:
A mixture of 4.0 g (15.7 mmol) of N-(4-methoxyphenethyl)benzamide and 21.1 ml (227.0 mmol) of POCl3 in MeCN (120 ml) was refluxed for 16 h. The mixture was then concentrated to small volume under vacuum, taken up with MeOH and concentrated to small volume under vacuum again. This step was repeated three times. 24.65 g of the crude product 7-methoxy-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)#[N:2].CC(OC(C)=O)=O.[N+:22]([O-])([OH:24])=[O:23]>O>[C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(C)C#N)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)C#N)cc1[N+](=O)[O-]

Procedure:
To the flask of N-[4-(Cyano-methyl-methyl)-phenyl]-acetamide (12.9 g, 68.5 mmol) was added Ac2O (35 mL) at 5° C. The mixture was stirred and added HNO3 (7.45 g, 70.9 mmol) at 0° C. This reaction was very exothermic. The mixture was stirred for 1 hr at 0° C. and additionally stirred for 3 hrs at room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[CH:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cn1cnc(C(=O)O)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cn(C)cn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:18])[C:9](=[O:10])[CH2:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.CC(C)([O-])C.[K+].[CH3:25][N:26]=[C:27]=[S:28]>CN(C)C=O>[OH:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])([CH3:18])[O:5][C:6]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=2[C:8]=1[C:27](=[S:28])[NH:26][CH3:25]
Reactant: COCC1(C)Oc2ccc([N+](=O)[O-])cc2CC1=O
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 5 g of 3,4-dihydro-2-methoxymethyl-2-methyl-6-nitro-2H-1-benzopyran-3-one and 60 ml of dried N,N-dimethylformamide was added 2.5 g of potassium tertiary butoxide under nitrogen stream with stirring under ice-cooling and the mixture was stirred for 5 minutes. Then, 1.7 ml of methyl isothiocyanate in 3 ml of N,N-dimethylformamide was added to the mixture and it was stirred at 5° C. for 18 hours. Ice water was added to the mixture and it was washed with ether. A water layer was acidified to be hydrochloric acid and extracted with ether. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=3:1) to obtain 5.1 g of 3-hydroxy-2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 139°-141° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=C(C=CC=1)C(OC)=O>>[CH3:13][O:14][C:8]1[CH:7]=[C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OC)c1
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1cccc(C(C)(C)N)c1
Yield: 31 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 3-methoxybenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 31%.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[CH:11]=2)[CH:2]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example 28, 65 mg of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[3-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 7 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1](#[N:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C>[NH2:16][C:1]1[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:19][N:18]=1
Reactant: CCCCCCCCCCCCC#CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cc(N)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 2 -pentadecynenitrile (2.9 g, 13.2 mmol) in ethanol (60 mL) was added to a stirred solution of hydroxylamine hydrochloride (1.1 g, 15.8 mmol) in 1.0 N NaOH (29.1 mL, 29.1 mmol). The resulting mixture was stirred for 16 hours (25° C.). The resulting slurry was filtered and the crystals were washed with cold water and dried in a vacuum oven at 40° C. (24 hours) to yield 2.4 g (71.9%) of 3-amino-5-dodecyl-isoxazole as white platelets; m.p. 79.5°-81° C.
Reaction SMILES: [F:1][C:2]1([F:24])[C@@:7]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[O:15][C@:9]3([CH2:14][CH2:13][CH2:12][O:11][CH2:10]3)[CH2:8]2)[N:6]=[C:5]([NH2:23])[O:4][CH2:3]1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)#[N:26]>>[NH2:23][C:5]1[O:4][CH2:3][C:2]([F:1])([F:24])[C@:7]2([N:6]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=3)=[O:34])[CH:20]=1)[O:15][C@:9]1([CH2:14][CH2:13][CH2:12][O:11][CH2:10]1)[CH2:8]2
Reactant: NC1=N[C@@]2(C[C@@]3(CCCOC3)Oc3ccc(N)cc32)C(F)(F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(C[C@@]4(CCCOC4)O3)N=C(N)OCC2(F)F)nc1
Yield: 64 %

Procedure:
The condensation of (2′R,4R)-5,5-difluoro-5,5″,6,6″-tetrahydro-4″H-dispiro[1,3-oxazine-4,4′-chromene-2′,3″-pyran]-2,6′-diamine (intermediate B7.5) and 5-cyanopicolinic acid yielded the title compound (64% yield) as a yellow solid. MS (ISP): m/z=470.3 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:27]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)o2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-(N-acetylamino)phenylboronic acid, using tetrakis(triphenylphosphine)palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a yellow solid; MS (ES+) 354 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in CH2Cl2 (10 ml), triethylamine (3.88 ml) and methanesulfonyl chloride (1.08 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-methane sulfonyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.32 g).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:3]1=2.[K+].[Br-]>>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:3]1=2
Reactant: NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Br-]
Agent: [K+]
Product: NC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2

Procedure:
In a similar manner as above, 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboamide IX was prepared from the oxepin-carboamide VIII in a quantitative yield. Recrystallization from tetrahydrofuran gave pure crystals having a melting point of 257°-258° C. IR spectrum (KBr tablet, cm-1): 3350, 3180, 1665, 1625, 1410, 1255; NMR spectrum (CDCl3 +d6DMSO, δ-value, ppm): 5.10(d, 1H), 5.78, 5.85, 6.09 (each d, total 3H), 6.6-8.1(m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[NH:2]=[C:1]([N:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH:35]2[CH2:36][CH2:37][CH2:38][O:34]2)[CH2:45][CH2:44]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COC(CN2CCNCC2)C1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2CCCO2)CC1
Yield: 48 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(tetrahydro-2-furylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([OH:29])=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]O)=[CH:49][CH:48]=1>CS(C)=O.CN(C)C1C=CN=CC=1>[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][O:28][C:27]([CH2:26][C:8]2([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:31][CH2:32][CH3:33])[C:7]2=[O:30])=[O:29])=[CH:49][CH:48]=1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reactant: OCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)OCc2ccc(Br)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 18 h
Yield: 47.5 %

Procedure:
In 10 ml of dimethyl sulfoxide was dissolved 0.336 g of (+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one. To the solution were added successively 0.108 g of 4-dimethylaminopyridine, 0.170 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.166 g of 4-bromobenzyl alcohol. The resulting mixture was stirred for 18 hours, followed by concentration. The concentrate was diluted with ethyl ether, washed successively with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.219 g (48%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=O)[C:10](=[N:18]O)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[CH3:22][NH:23][NH2:24]>CO>[NH2:18][C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:24][N:23]([CH3:22])[C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CNN
Reactant: CCOC(=O)C(=O)C(=NO)C(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(-c2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(2,6-dichlorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate (14 g, 44 mmol) in MeOH (400 mL) at 0° C., add dropwise-concentrated HCl (10 mL) followed by methyl hydrazine (2.02 g, 44 mmol). Stir the reaction mixture at ambient temperature for 8 h and concentrate in vacuo. Partition the residue between EtOAc (400 mL) and saturated aqueous NaHCO3 (150 mL) and separate the layers. Add water (200 mL) to the organic layer, followed by sodium hydrosulfite (150 g) and stir the resulting mixture vigorously for 4 h. Separate the organic phase, wash with water (200 mL), brine (200 mL), dry over MgSO4 and evaporate to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 84.1 %

Procedure:
4-Nitrobenzaldehyde (760 mg) and 3,4-dimethoxybenzyl cyanide (890 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (1.31 g, yield: 85%).
Reaction SMILES: Cl[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)CCC>C1(C)C=CC=CC=1.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>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(Cl)n1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2nc3ccccc3s2)n1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A reaction tube charged with 6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (20.0 mg, 0.056 mmol) and Pd(PPh3)4 (6.5 mg, 0.0056 mmol) is purged with nitrogen. A solution of 2-tributylstannanyl-benzothiazole (47.6 mg, 0.112 mmol) in anhydrous toluene (1.0 mL) is added via syringe. The reaction mixture is heated at 100° C. for 2 days. After removal of the solvent, the residue is purified by preparative LCMS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.21 (d, 2H), 7.90 (t, 1H), 7.69 (t, 1H), 7.59 (t, 2H), 7.46-7.40 (m, 5H), 7.24 (d, 2H); HPLC-MS calculated for C24H14ClN5OS (M+H+) 456.1. Found 456.1.