Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=[C:8]2[C:7]=1[OH:23])=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:26]=1[S:36]([NH2:39])(=[O:38])=[O:37].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:21]([C:19]1[CH:20]=[C:8]2[C:7]([OH:23])=[C:6]([C:4]3[NH:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][C:26]=4[S:36](=[O:38])(=[O:37])[N:39]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1)#[N:22]
Reactant: CCOC(=O)c1c(O)c2cc(C#N)cn2n(CCC(C)C)c1=O
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cc(C#N)cn21
Temperature: 120 °C
Yield: 6.7 %

Procedure:
A solution of 6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 15e, 0.25 g, 0.788 mmol) and 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 3d, 0.209 g, 0.788 mmol) in pyridine (4 mL) was heated to 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. The reaction mixture was passed through a plug of silica gel and eluted with 50%→100% ethyl acetate in hexanes. The solvents were removed in vacuo and purification by preparative HPLC (Column Luna 5μ C18 (2) 100 Å size 150×21.2 mm, 5 micron, 40%-95% in 11 min 25 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, N-{3-[6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0275 g, 0.0531 mmol, 6.7% yield). 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (3H, s), 0.96 (3H, s), 1.17-1.23 (2H, m), 1.51-1.57 (2H, m), 1.65-1.75 (1H, m), 5.74 (1H, s), 3.05 (3H, s), 7.40 (1H, s), 7.49-7.57 (3H, m), 8.51 (1H, s), 10.12 (1H, s), 13.75 (1H, s). LC-MS (ESI) calcd for C21H22N6O6S2 518.10. found 519.4 [M+H+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=1)=O)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 138.1 %

Procedure:
Triphenylphosphine (2.29 g, 8.73 mmol) and diisopropylazodicorboxylate (1.76 g, 8.70 mmol) were added to a solution of 2-{[3-cyano-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 38, 1.0 g, 3.49 mmol) in THF (20 mL), at 0° C. The reaction mixture was stirred for 30 min at 0° C. and trimethylsilyl azide (1.01 g, 8.77 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then heated to reflux for 4 h. The reaction mixture was diluted with EtOAc and washed with ice water, followed by saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 10%-50% EtOAc/pet.ether, to give the title compound (1.5 g, impure).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24]I>>[CH3:24][N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CI
Product: CN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a yellow semi-solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and methyl iodide. MS (ESI): 343.1 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([N:19]([C@@H:16]2[CH2:17][CH2:18][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([OH:4])[CH2:6][CH2:7]3)=[O:12])[CH2:14][C@H:15]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH3:20])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(=O)O[C@H]1CC[C@H](C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCC(O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of the compound obtained in Example 518 (0.103 g) in methanol (1.8 mL) was added sodium carbonate (0.067 g) and the mixture was stirred at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (0.076 g, 80%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1Cl
Yield: 41.8 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (82 mg, 42%). MS (ISP) 393.1 [(M+H)+]; mp 265° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:27])[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2].C=O.[C:30]([BH3-])#N.[Na+]>CO>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([CH3:30])[CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:27])[CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(sc(NC(=O)C(c3ccccc3)c3ccccc3)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-2,2-diphenyl-acetamide (prepared in Example 8, step 1; 75 mg; 0.15 mmol) and formaldehyde (0.1 mL of 37% solution) in dry methanol at room temperature was added sodium cyanoborohydride (14.5 mg; 0.23 mmol). The mixture was allowed to stir for 1 hour at room temperature then concentrated in vacuo. The residue was taken up into methylene chloride and washed with water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 50 mg (85%) of N-(3-Cyano-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-2,2-diphenyl-acetamide. ES-HRMS m/e calcd for C23H21N3OS (M+H+) 388.1478, found 388.1481.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:12]([OH:14])=[O:13])(=[O:17])[CH3:16]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)cc(C(=O)O)n2C(C)=O
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 20 g of 5-methoxyindole-2-carboxylic acid (J. Chem. Soc. 1970, 865) and 200 ml of acetic anhydride is refluxed for 2 hours and allowed to cool to room temperature. It is filtered, the filtrate evaporated and the residue is stirred in 300 ml of water. Excess sodium bicarbonate is added, the mixture stirred for 3 hours and then washed with 200 ml of diethyl ether. The aqueous layer is acidified to pH=1 with concentrated hydrochloric acid and filtration yields the 1-acetyl-5-methoxyindole-2-carboxylic acid melting at 173°-175°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[CH3:48][C:49]([CH:52]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53]1)([OH:51])[CH3:50]>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:54]2[CH2:55][CH2:56][CH2:57][CH:52]([C:49]([OH:51])([CH3:50])[CH3:48])[CH2:53]2)=[O:16])=[CH:7][CH:8]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(O)C1CCCN(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(1-methyl-1-hydroxyethyl)piperidine hydrochloride (25 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (23 mg). HRMS (ESI, pos. ion) m/z calcd for C19H21F3N2O3: 382.1504, found 382.1502.
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:18]([O:17][C:16]([N:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:9][CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)CCNCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Next, tetrahydrofuran (8 ml) was added to 3-[N-(2-cyclohexylethyl)amino]propionic acid hydrochloride (1.0 g, 4.2 mmol), and the mixture was stirred at room temperature. Di-t-butyl carbonate (1.1 g, 5.1 mmol) and triethylamine (1.3 ml, 9.3 mmol) were added to the mixture, the whole was stirred overnight, and then a 5% aqueous citric acid solution (10 ml) was added to the reaction mixture. The whole was extracted with chloroform (60 ml), and the obtained organic layer was washed with saturated brine (20 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.79 g, 62%) as a colorless oily matter.
Reaction SMILES: [CH:1]1([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:20]1([N:26]2[C:30]3([CH2:31][CH2:32][N:33]([CH2:16][C:15]4[CH:18]=[CH:19][C:12]([O:11][CH:1]5[C:10]6[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=6)[CH2:4][CH2:3][CH2:2]5)=[CH:13][CH:14]=4)[CH2:34][CH2:35]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=Cc1ccc(OC2CCCc3ccccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccc(OC3CCCc4ccccc43)cc1)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 4-(1,2,3,4-tetrahydro-1-naphthyloxy)benzaldehyde (264 mg, 1.05 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (232 mg, 1.00 mmol) in 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (369 mg, 1.74 mmol). The resultant reaction mixture was stirred at room temperature under argon atmosphere for 20 h. The reaction mixture was quenched with 1N aqueous NaHCO3 and extracted with CHCl3 (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (4% MeOH in CHCl3) to yield the title product as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[Na].[CH3:15][OH:16]>>[CH3:15][O:16][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cncnc1Cl
Reactant: CO
Agent: [Na]
Product: COC(=O)Cc1cncnc1OC
Temperature: 120 °C
Yield: 93 %

Procedure:
To a solution of 0.250 g (1.25 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate (see i-48, Step A) in 10 mL of absolute methanol was dissolved 0.060 g (2.50 mmol) of sodium metal. The resulting solution was heated under microwave conditions at 120° C. for 10 min. All volatiles were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a clear gum (0.21 g, 93%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 3.96 (s, 2H), 4.01 (s, 3H), 3.70 (s, 3H), 3.57 (s, 2H). LC-MS: m/z (E/S) 183 (MH)+.
Reaction SMILES: [Na].[C:2]([C:4]1[C:9](=[S:10])[NH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])#[N:3].[CH3:33]I>CO>[C:2]([C:4]1[C:9]([S:10][CH3:33])=[N:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[C:6]([C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:3]
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc(SC)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 59 %

Procedure:
69 mg (3 mmol) of sodium is added at room temperature in small portions to 0.4 ml of methanol. After the sodium disappears, 870 mg (2 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate is added. The reaction mixture is stirred for 5 minutes, and then 0.18 ml (3 mmol) of methyl iodide is added and stirring is continued for 3 hours. The solvent is concentrated and the precipitate formed is filtered, rinsed with water and then diethyl ether and then dried under vacuum to yield 0.53 g (59%) of ethyl 5-cyano-2-(4-methoxyphenyl)-6-(methylthio)-4-(2-nitrophenyl)nicotinate in the form of a yellow powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:10])[N:7]([CH3:9])[N:8]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([O:22][C:23](=[O:24])[NH:10][C:6]2[N:7]([CH3:9])[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(C2CC2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C2CC2)cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamine (3.0 g, 22 mmol) (65 ml) and sodium bicarbonate (2 g, 24 mmol) in THF is cooled to 0° C. Phenylchloroformate (3.4 g, 22 mmol) is added dropwise over 15 minutes. The reaction mixture is allowed to warm to ambient temperature and stirred for 5 hours, then filtered and the filtrate partitioned between ethylacetate and water. The organic phase is washed with water, 5% aqueous citric acid solution and brine, dried over MgSO4 and evaporated to afford (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester. [M+H] 258.17.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:24][CH2:25][CH3:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:4]([CH2:24][CH2:25][CH3:26])=[N:3][C:2]=1[CH3:1]
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (8.44 g) and sodium acetate (2.22 g) in acetic acid (100 mL) was added bromine (1.39 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.68 g, 64%) as a colorless solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].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:5]([O:9][C:10](=[O:11])[NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:17][CH2:18]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isopropylamine (925 μL, 10.86 mmol) was added to a stirred solution of trans 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.32 g, 5.43 mmol), HATU (2.06 g, 5.43 mmol) and diisopropylethylamine (2.79 mL, 16.3 mmol) in DMF (50 ml). The resulting mixture was stirred at ambient temperature for 72 hours. The solvent was evaporated under vacuum and the residues diluted with water and extracted into DCM. The combined organic extracts were washed with 1M sodium hydroxide, water and brine, dried with magnesium sulfate and concentrated under vacuum affording 1.37 g (89%) of trans (4-isopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method B, ESI): RT=3.07 min, m+H+ MeCN=326.3; 1H NMR (400 MHz, DMSO) δ: 7.50 (d; 1H); 6.66 (d; 1H); 3.78 (m; 1H); 3.13 (m; 1H); 1.94 (m; 1H); 1.78 (d; 2H); 1.66 (d; 2H); 1.37 (s; 9H); 1.31 (m; 2H); 1.11 (m; 2H); 1.01 (d; 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH2:22]4)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH:12]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:16][CH2:15]2)[CH2:22]1)(=[O:39])[CH3:38]
Reactant: Clc1ccc2c(C3=CCN(CCCCC4CNc5ccccc54)CC3)c[nH]c2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC(CCCCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Temperature: 5 °C
Yield: 49.9 %

Procedure:
A mixture of 6-chloro-3-[1-[4-(2,3-dihydro-1H-indol-3-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 30b (4.9 g), triethylamine (3.7 g), and THF (200 ml) was cooled (5° C.), and the mixture was added a solution of acetyl chloride (1.0 g) in THF (50 ml). The reaction mixture was allowed to warm to room temperature, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (90:10:5) to give the crude product, which was recrystallized (methanol-ethyl acetate) to give the title compound (2.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:16][OH:17])[C:6](=[O:11])[C:5]2([CH3:13])[CH3:12]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Product: CC1(C)C(=O)N(CCO)c2ccc(Br)cc21

Procedure:
Prepared from 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, butyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][OH:19])=[N:13][C:12]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:11]2.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([NH:20][C:12]2[N:13]=[C:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=3)=[N:22]1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(CO)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MsCl (1.0 g) in 20 mL CH2Cl2 was added slowly to a mixture of [6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-methanol (11.0 g) and Et3N (1.42 g) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred at r.t. for 3 h, and then washed with saturated NaHCO3 (aq) and NaCl(aq). The organic layer was dried over Na2SO4, and concentrated to give the crude product.