Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:17][CH:16]([OH:18])[C:13]3([CH2:15][CH2:14]3)[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:17][C@@H:16]([OH:18])[C:13]4([CH2:14][CH2:15]4)[CH2:12]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:27])[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1nc(NN)c(F)c(N2CC(O)C3(CC3)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2C[C@@H](O)C3(CC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
5-(5-Fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-5-azaspiro[2.4]heptan-7-ol (82 mg, 0.324 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (115 mg, 0.27 mmol), and HOAt (44 mg, 0.324 mmol) were dissolved in 2 mL of DMF. NMM (0.089 mL, 0.81 mmol) was added, followed by EDC (62 mg, 0.324 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(7S)-7-hydroxy-5-azaspiro[2.4]hept-5-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (91 mg, 63%). LCMS: (M+H)+: 535.3.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([CH2:12][C:13](=[S:15])[NH2:14])#[N:11]>CN(C)C=O>[C:10]([CH2:12][C:13]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)#[N:11]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N#CCC(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(CC#N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a solution of ethyl 3-bromo-2-oxopropanate (21 g, 110 mmol) in N,N-dimethylformamide (50 mL) was added a solution of 2-cyanoethanethioamide (10 g, 100 mmol) in N,N-dimethylformamide (50 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (5.1 g, 26%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2](=[O:33])[CH2:3][N:4]([CH3:32])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:30][CH3:31])=[CH:12][N:13]2[C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:39]>>[NH2:1][C:2](=[O:33])[CH2:3][N:4]([CH3:32])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:30]([CH3:31])=[O:39])=[CH:12][N:13]2[C:16]2[N:17]=[CH:18][C:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)=[CH:20][N:21]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Product: COc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1

Procedure:
Oxidation of 283a) with m-chloroperoxybenzoic acid (0.18 g, 0.39 mmol). White solid. Yield: 0.065 g (35% of theory)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.CN1CCOCC1.[C:18](OCC1C=CC=CC=1)(=[O:21])[C:19]#[CH:20]>C1COCC1>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]3[C:4]=2[O:10][CH2:20][CH2:19][C:18]3=[O:21])[O:9]1
Reactant: Oc1cccc2c1OCO2
Reactant: C#CC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CCOc2c1ccc1c2OCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-methylenedioxyphenol (27 g) and N-methyl morpholine (19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over a period of 30 minutes with cooling. After the addition was complete the reaction was stirred at room temperature for 1.5 hours followed by concentration The residue was taken up into Et2O (500 ml), washed with 10% HCl (2×100 ml), dried over MgSO4. filtered and concentrated. This material was subjected to hydrogenation with 10%Pd/C in methanol at 4 atm. The reaction was filtered and concentrated. The resulting saturated acid was dissolved into methanesulfonic acid (350 ml) and stirred for 24 hours. The reaction was poured onto ice and extracted with CH2Cl2. The organic layer was washed with saturated Na2CO3, dried over MgSO4, filtered and concentrated to provide the desired material.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]2)=[N:35][CH:36]=1)#[N:30]>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:43]([CH:40]3[CH2:39][CH2:38][N:37]([C:34]4[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=4)[CH2:42][CH2:41]3)=[O:44])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 652.3 [M]+.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=1[S:17](Cl)(=[O:19])=[O:18]>O>[CH3:2][O:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=1[S:17](=[O:19])(=[O:18])[NH2:1]
Reactant: N
Reactant: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1OCCO2
Solvent: O
Product: COc1c(S(N)(=O)=O)cc(C(=O)O)c2c1OCCO2
Yield: 79.2 %

Procedure:
300 g of 34% ammonia were introduced into a balloon flask provided with an agitator and a thermometer and then 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 0°-5° C. The mixture was agitated and then the precipitate was dissolved in water. The solution was filtered and treated with 280 cm3 of concentrated hydrochloric acid. The precipitate was dried off, washed and dried. 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 247°-248° C.; yield: 82%).
Reaction SMILES: C(OC(=O)[C@H](CC1C=CC(O)=CC=1)N)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C([O:41][C:42](=[O:63])[C@H:43]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=1)[NH:44][C:45](=[O:54])[CH:46]([CH3:53])[CH2:47][CH2:48][C:49]([O:51]C)=[O:50])C1C=CC=CC=1.COC(CCC(C)C(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O)=O>>[C:49]([CH2:48][CH2:47][CH:46]([CH3:53])[C:45]([NH:44][C@H:43]([C:42]([OH:63])=[O:41])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([OH:62])=[CH:60][CH:61]=1)=[O:54])([OH:51])=[O:50]
Reactant: COC(=O)CCC(C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: COC(=O)CCC(C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Product: CC(CCC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
By substituting L-tyrosine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedure of Examples 24 and 26, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine benzyl ester, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine, and N-(4-carboxy-2-,ethylbutanoyl)-L-tyrosine are obtained.
Reaction SMILES: Cl.C[N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14]3)[CH2:5][CH2:4]1.[Cl:28]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[ClH:28].[C:22]1([S:19]([C:15]2[CH:16]=[N:17][C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[N:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A stirred solution of 8-(4-methyl-piperazin-1-yl)-3-phenylsulfonylquinoline hydrochloride (D10) (0.148 g, 0.4 mmol), 1-chloroethyl chloroformate (0.093 ml, 0.85 mmol) and N,N-diisopropylethylamine (0.148 ml, 0.85 mmol) in 1,2-dichloroethane (9 ml) was heated at reflux for 1.25 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane, pooling fractions which contained the major component (Rf 0.9, methanol/dichloromethane 1:19). The purified material was redissolved in methanol (15 ml) and the solution was refluxed for 1 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to a solid which was stirred with diethyl ether (5 ml) and filtered to afford the title compound (D11) (0.08 g, 0.21 mmol, 51%);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16](CC)CC)[CH3:15].ClCCN>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: NCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Yield: 26 %

Procedure:
A solution of N-tert-butoxycarbonyl-piperazin (5 g, 26.8 mmol), triethylamine (7.44 ml, 53.6 mmol), and chloroethylamine (3.11 g, 26.8 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 72 hours. The reaction mixture was filtered, partitioned between H2O and ethyl acetate. The aqueous phase was lyophilized, the residue stirred with methanol and the precipitate collected by suction. The precipitate was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia=9/1/0.1) to give 1.6 g (26%) of the desired product. MS m/z: 230 ((M+H)+, 91%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[O:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC(S([N:25]=[N+:26]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[OH-].[K+]>C(OCC)C.ClCCl>[C:1]([O:6][CH2:7][C:8]([O:9][C:10](=[O:15])[CH2:11][C:12](=[O:13])[CH3:14])=[N+:25]=[N-:26])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)C(=O)OCC(=[N+]=[N-])OC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
2-Diazo-3-oxobutyroxyethyl methacrylate was prepared according to the protocol described in Y. K. Rao et al., Indian J. Chem., 25B, 735 (1986). A mixture of 2-acetoacetoxyethyl methacrylate (4.28 g, 20 mmol, available from Eastman Chemical, Kingsport, Tenn.), dichloromethane (30 mL), and p-toluenesulfonyl azide (3.94 grams, 20 mmol) was cooled to 0° C and then DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 4.48 mL, 30 mmol) was added dropwise. After the addition of DBU, the reaction mixture was stirred at room temperature for 15 minutes and then poured into a mixture of 10% KOH (100 mL) and diethyl ether (50 mL). The organic layer was separated and the aqueous layer was re-extracted with diethyl ether (50 mL). The organic extracts were combined and then washed sequentially with 3N HCl (50 mL), deionized water (2×50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 4.39 grams of 2-diazo-3-oxobutyroxyethyl methacrylate as a pale yellow oil. 1H NMR (400 MHz, CDCl3)δ1.94 (s, 3H); 2.47 (s, 3H); 4.35-4.55 (m, 4H); 5.60 (s, 1H); 6.12 (s, 1H) IR: 2181 cm4. Decomposition temperature: 156° C. (by DSC).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][OH:15])[CH:22]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
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: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2cccc(CO)c2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-isopropyl-8-Bromoquinoline (11.1 g, 44.4 mmol) (described in International Patent Publication WO 94/22852), 3-(hydroxymethyl)phenylboronic acid (8.70 g, 57.2 mmol), Na2CO3 (2M, 71 mL, 142 mmol) and Pd(PPh3)4 (2.51 mg, 2.17 mmol) in 280 mL of DME was stirred at 80° C. for 5 h. The resulting mixture was cooled to r.t., diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex/EtOAc, 1/1) and stirring in CH2Cl2/hexane (1/9) yielded 6-Isopropyl-8-[3-(hydroxymethyl)phenyl]quinoline as a white solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:13](Cl)=[O:14])([CH3:9])([CH3:8])[CH3:7]>>[CH2:1]([NH:5][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCCCN
Product: CCCCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, n-butylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoyl chloride to produce N-n-butyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 181°-183°C. When tested by the procedure in Example 2, the sample containing this compound lasted 950 hours, about 3.2 times as long as the control.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][NH:21][CH2:22][C:23]#[CH:24]>>[CH3:20][N:21]([CH2:22][C:23]#[CH:24])[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C#CCNC
Product: C#CCN(C)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
Analogously to Example C, using 27.3 g (0.1 mol) of 11-chlorocarbonyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 7.0 g (0.1 mol) of N-methyl-propargylamine, 27 g (88% of theory) of the desired compound are obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21]C(=O)C)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl>[NH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:19][CH:18]=1
Reactant: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Yield: 59.2 %

Procedure:
N-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide (2.6 g) was dissolved in 10% hydrochloric acid (50 ml) and the mixture was refluxed under heating for 6 hr. To the mixture was added 10% aqueous sodium hydroxide solution to make it alkaline and the mixture was extracted with ethyl acetate (100 ml×3). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was crystallized from water-ethanol to give the title compound (1.34 g) as white crystals, m.p.=68-70° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][CH:19]=[C:20](Cl)[C:11]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:20]2[C:11]3[C:10]4[CH2:9][NH:8][CH2:16][CH2:15][C:14]=4[NH:13][C:12]=3[N:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3nccc(Cl)c3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Product: COc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
4-Chloro-5,7,8,9-tetrahydro-dipyrido[2,3-b;3′,4′-d]pyrrole-6-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), p-anisidine (80 mg, 0.65 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (12 mg, 0.03 mmol), and KOH (55 mg, 0.97 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 95° C. The crude product was purified directly via prep-LC-MS to provide 47 (3 mg, 3% yield) as a tan solid. LC-MS (M+H=295, obsd.=295).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH:10]=[CH2:11])=[CH:6][CH:7]=1.[C:15]([NH:20][NH2:21])([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:15]([NH:20][NH:21][C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH:10]=[CH2:11])=[CH:6][CH:7]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C=CCN(CC=C)c1ccc(Cl)nn1
Reactant: CCOC(=O)NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCN(CC=C)c1ccc(NNC(=O)OCC)nn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 4.18 g (0.02 moles) 3-chloro-6-diallylaminopyridazine and 4.16 g (0.04 moles) monocarbethoxyhydrazine is warmed up to 140° C and kept at this temperature for 1 hour. The mixture is taken up with cool water and sodium carbonate is added until neutral pH. It is then extracted with methylene chloride, the organic extracts collected together, dried over sodium sulphate and concentrated. The residual oil is purified by chromatography on silica gel column, eluting with a mixture of chloroform-methanol 9.5:0.5. The unitary fractions on thin layer chromatography with the same Rf are collected together; the solvent is eliminated by evaporation and a yellow oil formed by a 3-(2-carbethoxyhydrazino)-6-diallylaminopyridazine is obtained.
Reaction SMILES: O.C([O:9][C:10]1[C:11]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:12][C:13]([CH2:40][CH3:41])=[C:14]([CH:39]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:40]([C:13]1[CH:12]=[C:11]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[C:10]([OH:9])=[CH:39][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)[CH3:41]
Reactant: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Yield: 112.3 %

Procedure:
Hydrogenate a slurry of 10% palladium on charcoal, 50% wet (with water by weight) (13 g) and 4-[[3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-phenyl]amino]-2,2-dimethyl-4-oxo-butanoic acid (260 g, 405 mmol)) in THF (1560 mL) starting at a hydrogen pressure of 900 psi. Continue the hydrogenation 20 h while not adding additional hydrogen. Hydrogenate two additional days maintaining hydrogen pressure of 200 psi. Filter the mixture through diatomaceous earth and concentrate the filtrate in vacuo to yield the title compound (251 g, quantitative) as a solid. Excess weight is due to the presence of THF. ES/MS m/z 552 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.ClC1C(C=O)=C[N:17]=[C:16]2N([Si](C(C)C)(C(C)C)C(C)C)C=CC=12.CN>COC(O)C>[CH3:16][NH:17][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: CN
Agent: COC(C)O
Product: CNc1c(C=O)cnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde and 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.0 g, from above step), methylamine (40% solution in water, 16 mL, 100 mmol) in methoxy-ethanol (4 mL) is heated at 110° C. in a sealed tube overnight. The reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 20 mL) and heated at 50° C. After stirring for 1.5 hours at 50° C., the reaction mixture is neutralized with saturated sodium bicarbonate solution to a pH of 8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a light yellow solid: MS m/z 176.1 (M+1).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[C:23]([C:28](O)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:20]([F:19])([F:31])[O:21][C:22]1[C:23]([C:28]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ncccc1OC(F)(F)F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1OC(F)(F)F

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 70 mg, 0.25 mmol), 3-(trifluoromethoxy)pyridine-2-carboxylic acid (CAS number 1221171-81-8; 86 mg, 0.42 mmol), EDC (71 mg, 0.37 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (51 mg, 0.37 mmol) and triethylamine (0.104 ml, 0.74 mmol) in DCM (1 ml) was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (25 ml) and water (10 ml). The organics were washed with water (2×10 ml) and brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.