Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18](O)([CH2:19]3)[CH2:17]1)[CH2:23]2)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1.C(N(CC)C(C)C)(C)C.C(OCC)(=[O:48])C>C(#N)C>[C:32]([C@@H:33]1[CH2:34][C@H:35]2[C@H:31]([CH2:36]2)[N:30]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:48])([CH2:19]3)[CH2:17]1)[CH2:23]2)#[N:28]
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reactant: CCOC(C)=O
Reactant: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
(2S)-2-{[(Benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV (20 gm), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile PTSA salt of Formula-XIII (16 gm), 1-ethyl-3-(3-dimethylaminoporpyl)carbodiimide (12 gm) and 1-hydroxy benzotriazole (1.2 gm) were dissolved in ethyl acetate (20 ml) and acetonitrile (40 ml). The reaction mixture was cooled to 20° C. Then addition of N,N-diisopropylethylamine (16 gm) was carried out for 15 min. The reaction mixture was stirred for 8 hrs and washed with 2N HCl solution. Organic phase was washed with NaHCO3 solution, dried and evaporated to yield 19.8 gm (80%) of title product. MP: 105-106° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.O[CH2:21][C@H:22]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:12]([C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[C:9]([O:11][CH2:21][C@H:22]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCCC(=O)N[C@@H](CO)c1ccccc1
Reactant: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](COC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of (S)-2-(2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (684 mg, 3.19 mmol) in DMF (25 mL) cooled in an ice/water bath was added EDC (612 mg, 3.19 mmol) and the resulting solution was stirred for 30 min. (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide (700 mg, 3.19 mmol), iPr2NEt (1.77 mL, 9.58 mmol), and DMAP (39.0 mg, 0.319 mmol) were subsequently added and the reaction mixture was stirred 16 h at which point LC-MS analysis indicated the presence of both starting material and desired product. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous layer was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 340 mg of product as a colorless oil in 26% yield. LRMS (M+Na)+: 438.4.
Reaction SMILES: I.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[NH:17][C:18](SC)=[NH:19].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][CH:32]=1)[C:28](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:59][NH2:60]>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:28]1[NH:60][N:59]=[C:18]([NH:17][C:4]2[CH:5]=[C:6]([O:15][CH3:16])[C:7]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[CH:8][C:3]=2[F:2])[N:19]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([F:40])([F:41])[F:42])=[CH:33][CH:32]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)c(F)cc1-n1cnc(C)n1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)c(F)cc1-n1cnc(C)n1

Procedure:
Methyl 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (1.50 g, 3.54 mmol, from preparation B) and 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (1.21 g, 3.72 mmol, from preparation AW) were coupled [N-methylmorpholine (1.95 mL, 17.7 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.560 mL, 17.7 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown foamy solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 568.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][NH2:52])[CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:52][CH2:51][CH2:50][N:47]2[CH2:48][CH2:49][O:44][CH2:45][CH2:46]2)=[O:35])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCOCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (140 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-morpholino-1-ethanamine (61 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (165 mg, yield 100%).
Reaction SMILES: [OH-].[K+].C[NH:4][C:5](=[NH:7])S.OS(O)(=O)=O.[CH3:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH2:20][C:21](OCC)=[O:22])=[O:19])=[CH:16][CH:15]=1>O>[NH2:7][C:5]1[O:19][C:18]([C:17]2[CH:26]=[CH:27][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:20][C:21](=[O:22])[N:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(=O)nc(N)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Potassium hydroxide (12.55 g, 224 mmol) was added to the vigorously stirred solution of methylthiopseudourea.H2SO4 (14.57 g, 52 mmol) in water (80 ml). Ethyl (4-methyl)benzoylacetate (20.0 g, 97 mmol) (obtained in preparation 1) was added to it and stirred at room temperature for 18 hours. The solid thus obtained was filtered, washed with water, ether and dried at 60° C. in vacuum to yield the title compound (1.85 g, 9.5%). 1H-NMR (DMSO-d6): δ 2.37 (s, 3H), 6.46 (s, 1H), 7.33-7.35 (d, 2H), 7.76-7.78 (d, 2H), 7.91 (bs, 2H, D2O exchangeable). MS m/z: 203.1 (M+).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (4.59 g, 30 mmol), triethylamine (12.5 ml, 90 mmol) in CH2Cl2 (50 ml) was added benzenesulfonyl chloride (5.30 g, 30 mmol). The mixture was stirred at 25° C. for 16 h. After evaporation of solvents, the residue was triturated with water (100 ml), filtered, and further purified by recrystallization from hexanes/CH2Cl2 (3:1) to afford the desired ketone (5.97 g, 83%) as a colorless solid. mp 116-118° C.; 1H NMR (500 MHz, CDCl3) δ2.54 (t, J=6.4 Hz, 4H), 3.41(t, J=6.4 Hz, 4H). 7.58 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[N+:12]([O-:15])([OH:14])=[O:13]>O>[N+:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:7])([O-:14])=[O:13].[N+:12]([C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1)([O-:15])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100 mL three-necked reaction flask fitted with reverse dean-stark apparatus was charged with 9.214 g toluene (0.1 mol), 40 mL 1,2 dichloro ethane, and 1.842 g of catalyst as prepared in example 5. The flask was flushed with nitrogen. The reaction mixture was refluxed at 100° C. for 1 h followed by dropwise addition of 8.6 mL (0.133 mol) of 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this reaction 80.5% toluene conversion was obtained with 54.7% selectivity for 2-nitro toluene and 41.6% for 4-nitro toluene. Other products were 3.7%.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[OH-].[Na+]>CCO>[CH3:9][C:8]1[C:3]2[C:1]([NH2:2])=[N:14][S:11](=[O:13])(=[O:12])[NH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2-cyano-3-methylphenyl)sulfamide (Example 24a) (211 mg, 1.0 mmol) in EtOH was treated with NaOH (2.0 N, 1.0 mL, 2.0 mmol) and the resultant solution was heated to 100° C. and stirred at that temperature for 0.5 h. After cooling to room temperature, the clear reaction solution was filtered and the filtration was carefully neutralized with 10% AcOH while with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and 20% EtOH in water to give the title product 5-Methyl-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H), 6.85-6.87 (d, J=8.4 Hz, 1H), 6.92-6.94 (d, J=7.2 Hz, 1H), 7.24 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 8.24 (s, 1H), 10.76 (s, 1H). MS 212 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39]O)[CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(Cl)Cl.O>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:32]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Reaction time: 2 h

Procedure:
Cool a mixture of phthalimide (5.4 g, 37 mmol) and PPh3 (9.6 g, 37 mmol) in tetrahydrofuran (80 mL) to 0° C. Add dropwise a solution of 3-pyridine propanol (5.0 g, 37 mmol) and diethyl azodicarboxylate (5.8 mL, 37 mmol) in tetrahydrofuran (50 mL). After 2 hours, dilute the reaction mixture with methylene chloride (100 mL), and water (100 mL). Wash the organic layer with water (100 mL), then brine (100 mL). Dry over magnesium sulfate, filter and concentrate to afford 2-(3-pyridin-3-yl-propyl)isoindole-1,3-dione as a yellow solid which can be used without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].N1CCCCC1>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:24]3[S:18][C:19](=[S:20])[NH:21][C:22]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(Nc1ccccc1)Nc1nc(C=C2SC(=S)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.6 g of rhodanine, 0.75 g of piperidine and 15 ml of ethanol. The resulting product was a yellow-brown powder having the following physical properties.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2F)[CH2:7]1.O.[C:27](OCC)(=[O:29])C>CO>[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2[O:29][CH3:27])[CH2:7]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1OC
Yield: 59.1 %

Procedure:
4.3 g (22.5 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 5.4 g (15.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 30 ml of methanol. The mixture was heated for refluxing for 8 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: 59.1%) of 5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:17]=[CH:16][C:10]3[NH:11][C:12]([CH2:14][OH:15])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-:19].[K+].[K+].[Mn]([O-])(=O)(=O)=[O:25].[K+]>O>[OH2:15].[OH2:19].[N:1]1([CH2:6][C:7]2[CH:17]=[CH:16][C:10]3[NH:11][C:12]([C:14]([OH:25])=[O:15])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1nc2cc(Cn3ccnc3)ccc2[nH]1
Agent: [K+]
Solvent: O
Product: O=C(O)c1nc2cc(Cn3ccnc3)ccc2[nH]1
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
To a stirred and heated (60° C.) solution of 8 parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole-2-methanol, 4.7 parts of potassium carbonate and 100 parts of water were added portionwise 11.1 parts of potassium permanganate. Upon completion, stirring was continued for 15 minutes at 60° C. The manganese(IV) oxide was filtered off over diatomaceous earth. After cooling, the filtrate was treated with glacial acetic acid to pH 5.5. The whole was evaporated to dry. The residue was taken up in a small amount of water. The product was filtered off and dried for 24 hours, yielding 3.1 parts (31.8%) of 5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole-2-carboxylic acid dihydrate (compound 265).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[O:22])[C:20]#[N:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(N(CC)CC)C>C(O)(=O)C.[Pd].ClCCl>[Cl:23][CH2:24][C:25]([NH:21][CH2:20][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:22])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c(C(=O)C#N)cn(CC3CCCCC3)c12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cccc2c(C(=O)CNC(=O)CCl)cn(CC3CCCCC3)c12
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetonitrile (prepared as described in Example 28; 2.39 g, 8.06 mmol) in acetic acid (50 ml) under nitrogen was added 10% palladium on charcoal (240 mg). The reaction was placed under a hydrogen atmosphere and stirred overnight. The reaction mixture was then filtered through a pad of dicalite. The dicalite was washed with acetic acid and the combined filtrate evaporated to leave a red oil. The red oil was taken up in dichloromethane (50 ml) and to this was added chloroacetyl chloride (0.77 ml, 9.67 mmol) followed by triethylamine (3.4 ml, 24.2 mmol) dropwise. The reaction was stirred for 30 minutes and poured into a separating funnel. The organics were washed sequentially with 5% aqueous sodium carbonate (2×30 ml) and brine (30 ml). The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to leave a red/brown oil. The oil was purified by flash chromatography using 20-100% (v/v) dichloromethane in heptane followed by 25-50% (v/v) diethyl ether in heptane to afford 2-chloro-N-[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]-acetamide (2.32 g, 6.1 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.1 mol) was dissolved in 100 mL of DMF and treated with 14.2 mL (0.15 mol) of 2-bromopropane and 41.9 g (0.3 mol) of anhydrous potassium carbonate. The system was flushed with nitrogen, and the mixture was heated to 90° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with 200 mL of water and extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to give 20.5 g (99% yield) of 4 as an oil that was characterized by LCMS and HNMR.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[N:23]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:30][CH:31]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1)c1ccc(N2CCOCC2)nc1
Yield: 26.9 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 6-morpholin-4-ylnicotinic acid (81 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound (43.6 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: OB(O)c1cccnc1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1
Yield: 27 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 28 mg of pyridin-3-yl-3-boronic acid via General Procedure A to give 18.1 mg of 212. MS (Q1) 469.3 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1)(=O)[CH3:2].[C:11]([OH:15])(=O)[CH:12]=O.C(=O)([O-])[O-].[K+].[K+].O.[NH2:23][NH2:24]>CO.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:2]=[CH:12][C:11](=[O:15])[NH:23][N:24]=2)=[N:5][CH:6]=1
Reactant: NN
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1ccc(-c2ccc(Cl)cn2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of 5.05 g of 2-acetyl-5-chloropyridine (32.4 mmol) in 36 mL of methanol at room temperature was added 60 mL of water and 4.8 g of 50% glyoxylic acid (32.4 mmol). Potassium carbonate (8.96 g, 2 equivalents) was added carefully (foaming), and the reaction mixture was stirred overnight at room temperature under nitrogen. The next day, the slurry was partially stripped on the rotovap to remove methanol (maximum bath temperature 30° C.). The slurry was transferred to a separatory funnel and extracted twice with methylene chloride. The aqueous phase was transferred back to a round bottom flask and treated carefully with 13.7 mL of acetic acid (foaming) followed by 1.9 g of hydrazine hydrate (38 mmol). The reaction mixture was refluxed for 2 hours. It became very dark. While cooling, potassium carbonate was carefully added until the pH was 7. The reaction mixture was cooled to room temperature, then filtered and washed with water. The solids were dried in a vacuum oven at 50° C. The product was 4.13 g of a fine black solid. The NMR data is as follows: 300 MHz 1H NMR (DMSO d-6, TMS=0 ppm) 7.10 (d, 1H); 7.75 (d, 1H); 8.11 (d, 1H) 8.70 (d, 1H); 13.4 (bs, 1H). The yield of pyridazinone was 61%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:9]3[C:10]([C:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=1)=[N:11][C:12](Cl)=[CH:13][CH:14]=3.[C:22]([O-])(=O)[CH3:23].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>O1CCOCC1.O.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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:12]2[N:11]=[C:10]3[C:16]4([C:4]5[CH:3]=[C:2]([C:9]6[CH:10]=[N:11][CH:12]=[CH:22][CH:23]=6)[CH:7]=[CH:6][C:5]=5[O:8][C:9]3=[CH:14][CH:13]=2)[CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[CH:28]=1
Reactant: CC(=O)[O-]
Reactant: OB(O)c1cccnc1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(-c3cccnc3)nc12
Temperature: 110 °C

Procedure:
A mixture of the 8-bromo-2-chloro-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine (from step 6, 40.0 mg, 0.109 mmol), potassium acetate (27.3 μL, 0.436 mmol), dichlorobis(triphenyl-phosphine)palladium (ii) (3.83 mg, 5.46 μmol) and 3-pyridylboronic acid (40.2 mg, 0.327 mmol) in 1.5 ml of dioxane/water=2:1 was heated at 110° C. under microwave irradiation for 15 min. LCMS and TLC showed incomplete conversion after 15 min. The reaction was re-heated in the microwave at 130° C. for 20 additional min. After cooling, the reaction mixture was purified by column chromatography (SiO2, DCM to DCM/MeOH=100:1 to 100:5 to 100:10 to 100:20) to afford 2,8-di(pyridin-3-yl)-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as a gum. MS (M+1): 408.0; and 2-chloro-8-(pyridin-3-yl)-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine also as a gum. MS (M+1): 365.0.