Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC>CCCCCC>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(COc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
The target compound (2.76 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(a) using 4-fluorophenoxyacetic acid (1.70 g), oxalyl chloride (2.18 ml), (S)-4-benzyl-2-oxazolidinone (1.77 g) and a solution of n-butyl lithium in hexane (1.61N, 7.14 ml).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[CH3:53][O:54][C:55]1[CH:59]=[C:58]([C:60](O)=[O:61])[O:57][N:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:60]([C:58]1[O:57][N:56]=[C:55]([O:54][CH3:53])[CH:59]=1)=[O:61]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: COc1cc(C(=O)O)on1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCc2oc(=O)oc2C)on1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.7 %

Procedure:
EDCI (169 mg, 880 μmol) and HOBT (119 mg, 880 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (200 mg, 440 μmol) and 3-methoxyisoxazole-5-carboxylic acid (63 mg, 440 μmol) in DMF (10 mL). DIPEA (114 mg, 880 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (60 mg). LC-MS: 576.1 [M+H]+. 1H-NMR: (DMSO-d6) 2.14 (s, 3H), 3.21-3.19 (m, 2H), 3.91 (s, 3H), 4.17-4.11 (m, 2H), 4.31 (br, 1H), 4.98 (s, 2H), 5.57 (br, 1H), 6.73 (s, 1H), 7.57-7.34 (m, 7H), 10.07 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:33][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CCCCCN
Agent: [H-]
Agent: [Na+]
Product: CCCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and n-pentylamine (0.19 mL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C=Cc1ccccc1-c1cccc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccccc2C=CC(=O)O)c1C
Temperature: 25 °C
Yield: 101.6 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-acrylic acid ethyl ester (110 mg, 0.39 mmoles) in THF (3 ml)/2N NaOH (3 ml) was heated to 160° C. for 10 min in a microwave reactor. The mixture was cooled to rt and partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and concentrated to afford the desired acid (100 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[S:24][C:25]2[C:26]([N:31]=1)=[N:27][CH:28]=[CH:29][CH:30]=2>CC#N>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][C:23]3[S:24][C:25]4[C:26]([N:31]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(O)cc2s1
Reactant: Clc1nc2ncccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 6-hydroxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.18 g, 0.9 mmol) in MeCN (9 mL) was added Cs2CO3 (0.6 g, 1.8 mmol), 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (0.18 g, 0.9 mmol) and the reaction mixture was stirred (rt, 3 h). The reaction mixture was filtered and concentrated in vacuum to provide the title compound as pink solid (0.18 g, 60%). MS (ESI): mass calcd. for C11H10N2O3S2, 342.0; m/z found, 343.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.12-8.00 (m, 3H), 7.92 (d, J=8.8, 1H), 7.46 (dd, J=8.8, 2.2, 1H), 7.24-7.18 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[N:15]=[C:14]([C:16](O)=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[CH:11][CH:12]=2)[C:7]1=[O:21].CN(C)C=O.S(Cl)([Cl:33])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[N:15]=[C:14]([C:16]([Cl:33])=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[CH:11][CH:12]=2)[C:7]1=[O:21]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(C(=O)O)nn(Cc3ccc(Cl)c(Cl)c3)c(=O)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)Cl)nn(Cc3ccc(Cl)c(Cl)c3)c(=O)c2c1

Procedure:
A stirred mixture of 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid (1.9 g.) in thionyl chloride (10 ml.) containing dimethylformamide (0.1 ml.) was heated under reflux for 3 hours. The solution obtained was then evaporated. The residue was dissolved in dry toluene and the solution evaporated. This procedure was carried out three times to give 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid chloride in essentially quantitative yield as a solid, having a satisfactory IR spectrum.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)([O-])=O.[CH2:27]([C:29]([CH3:31])=O)[CH3:28]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][CH:27]([NH:3][C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)[CH2:29][CH3:31]
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reactant: CCC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C)Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.9 g (24 mmol) of sodium borohydride is added to a suspension of 2.8 g (12 mmol) of nickel dichloride hexahydrate in a solution, cooled to 0° C., of 2 g (6 mmol) of 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example 7, and 10 ml of methyl ethyl ketone in 50 ml of ethanol. This temperature of 0° C. is maintained for 30 minutes, the mixture is allowed to rise to room temperature, stirring is continued for 2 hours, the mixture is evaporated under vacuum, the residue is taken up with ethyl acetate and 1.22 g of 4-(2-butylamino)1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained in liquid form.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 59.4 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1.0 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.01 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.98 g of the expected product, which is used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH:12]([CH3:14])[CH3:13]>>[F:10][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CC(C)COc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: CC(C)COc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 60.1 %

Procedure:
The title compound (0.16 g) was prepared from 4-bromo-2,6-difluoroaniline (0.2 g, 0.96 mmol) and 3-isobutoxyphenylboronic acid (0.242 g, 1.2 mmol) as a yellow liquid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30]>>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:29]#[N:30])[CH2:42][CH2:41]2)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:27])([F:28])[F:26])(=[O:17])=[O:18]
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(C(=O)C2CN(S(=O)(=O)c3ccccc3C(F)(F)F)C(=O)N2c2ccccc2)CC1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11, step 4) was coupled with 1-(2-cyanophenyl)-piperazine to give the title compound as a colorless solid. MS: 583.5 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(N)ccc2n1-c1ccccc1

Procedure:
300 mg (0.97 mmol) of ethyl 5-nitro-1-phenyl-1H-indole-2-carboxylate from Example LVI are initially charged in 40 ml of ethyl acetate and 40 ml of ethanol. 365 mg (5.80 mmol) of ammonium formate and 102 mg of palladium on activated carbon (10%) are added. The mixture is heated to reflux, and at 50° C. gas evolves. After 4 hours at reflux, the mixture is cooled and filtered off through kieselguhr, which is washed with 500 ml of ethanol. The solvent is removed under reduced pressure and the residue is dried.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>CN(C=O)C>[C:3]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCOCC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a suspension of NaH (22.11 g, 552.1 mmol) in DMF (350 mL) is added ethyl cyanoacetate (23.5 mL, 195 mmol) at 0° C. over 25 min. The reaction mixture is warmed to room temperature for 2 h and it is cooled down to 0° C. again. A solution of 1-chloro-2-(2-chloroethoxy)ethane (31.1 mL, 265.4 mmol) in DMF (50 mL) is added and the reaction mixture is warmed to room temperature for 1 h. Then the reaction mixture is heated at 90° C. for 16 h before the reaction is quenched with ice cold water (180 mL). The mixture is extracted with EtOAc (2×200 mL) and the organic layers are combined, dried (Na2SO4) and concentrated. The crude compound is purified by fractional distillation under high vacuum to afford the title compound (10 g, 25%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=[O:20])=[CH:11]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[CH:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Clc1ccc(CBr)cc1
Product: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 92 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.98 g of 4-chlorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.42 g of 1-(4-chlorobenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 92%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[OH-].[K+].Cl[CH:16]([F:18])[F:17].O>CC(O)C>[F:17][CH:16]([F:18])[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]([F:11])([F:10])[F:12])[C:5]=1[CH3:8]
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Into 78.6 g (436.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 500 ml of 2-propanol was added 153.1 g (2728.6 mmol) of powdery potassium hydroxide at room temperature, followed by stirring. Furthermore, an excess amount of chlorodifluoromethane was introduced into the reaction solution under stirring. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 88.9 g (yield: 88.5%) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=[O:23].[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:14][CH:13]=2)=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=[O:23]
Reactant: Cn1c(-c2ccc(OCC3CO3)cc2)cc2ncccc2c1=O
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(-c2cc3ncccc3c(=O)n2C)cc1
Yield: 92 %

Procedure:
6-Methyl-7-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1,6-naphthyridin-5(6H)-one was prepared analogous to Example 1b from 6-methyl-7-[4-(2,3-epoxypropoxy)-phenyl]-1,6-naphthyridin-5(6H)-one and isopropylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:10][C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]([CH3:25])[C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(=O)N1C
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 100 g (0.33 mole) of (±) 5,5-diethoxycarbonyl-4-phenylpyrrolidin-2-one in 500 ml of absolute dimethylformamide was added dropwise to a suspension of 9.64 g (0.36 mole) of sodium hydride in 200 ml of absolute dimethylformamide at room temperature under an N2 atmosphere. The mixture was subsequently stirred at room temperature until the evolution of gas had ended, a solution of 93.7 g (0.66 mole) of methyl iodide in 50 ml of absolute dimethylformamide was then added and the mixture was stirred at room temperature until all the starting material had reacted (about 1 hour, thin layer chromatography check). The reaction mixture was poured into 2 l of buffer solution, pH=7, and extracted five times with 600 ml of diethyl ether each time. Drying of the organic extracts (MgSO4) and stripping off of the solvent in vacuo gave 105 g (99.6%) of the title compound (95% pure according to (the 1H-NMR spectrum), which was further reacted directly. A sample was distilled in a bulb tube (boiling point0.5 : 240° C.) for analysis, Rf : 0.36 (toluene/ethyl acetate: 2/1),
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].C(N(C(C)C)CC)(C)C.[Br:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][CH:10]=1)[O:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[CH2:23][Br:22])#[N:9]
Reactant: O=C(Cl)CBr
Reactant: N#Cc1cccc(OCCN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCNC(=O)CBr)c1
Reaction time: 8 h

Procedure:
1.50 g (9.26 mmol) of 3-(2-aminoethoxy)benzonitrile and 1.77 ml (10.2 mmol) of diisopropylethylamine were dissolved in 15 ml of tetrahydrofuran. A solution of 0.92 ml (11.1 mmol) of bromoacetyl chloride in 5 ml of tetrahydrofuran was added to the obtained solution at 0° C., and they were stirred for 8 hours. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([OH:19])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[F:24][C:2]([F:23])([F:1])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([NH2:27])=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.2 %

Procedure:
10 g (29.7 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 50 ml of N,N-dimethylformamide and treated portionwise at room temperature with 5.1 g (31.2 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the clear brown solution was stirred at 50° for 20 min., cooled and treated dropwise with 8 ml of conc. ammonia at a temperature below 150 within about 15'. After stirring for 40 minutes the suspension obtained was poured into 300 ml of ice-water, whereupon the mixture was stirred at room temperature for 20', filtered and rinsed with a small amount of water. After drying there were obtained 7.51 g (75%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. >300°.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([C:17]([O:19]CC)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[C:1]([NH:9][CH2:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CNC(=O)c2ccccc2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCC1(C(=O)O)CCCCC1)c1ccccc1
Yield: 74.5 %

Procedure:
To a solution of ethyl 1-[(benzoylamino)methyl]cyclohexanecarboxylate (10.2 g, 35.1 mmol) in ethanol (50 ml) was added 50% aqueous potassium hydroxide solution (4 ml), and the mixture was heated under reflux for 6 hrs. Water (400 ml) was added and the reaction mixture was washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5N hydrochloric acid, the precipitate was collected by filtration, washed with water and dried at 50° C. under reduced pressure. Recrystallization from ethanol-toluene gave the title compound (6.83 g, 74%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:25]([CH3:26])=[C:11]2[C:12](=[O:24])[NH:13][C:14]3[CH:15]=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[CH:18][C:19]=3[C:10]2=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]([F:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[CH2:1]([N:8]1[C:25]([CH3:26])=[C:11]2[C:12](=[O:24])[N:13]([CH2:34][CH:35]([F:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[C:14]3[CH:15]=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[CH:18][C:19]=3[C:10]2=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c2c(=O)[nH]c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Reactant: CC(C)(C)OC(=O)NCC(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(CC(F)CNC(=O)OC(C)(C)C)c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-benzyl-3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-7) (8.0 g, 23 mmol, 1 equiv) and cesium carbonate (37 g, 110 mmol, 4.9 equiv) in DMF (100 mL) was added tert-butyl 3-bromo-2-fluoropropylcarbamate (1-9) (7.1 g, 27.7 mmol, 1.2 equiv) and the resulting mixture was stirred at 40° C. for 16 h. The reaction mixture was filtered and the filtrate concentrated and purified by silica gel chromatography (100% hexanes to 100% ethyl acetate over 1 h) to yield tert-butyl 3-(2-benzyl-3-methyl-4-oxo-2,4,7,8,9,10-hexahydro-5H-benzo[g]pyrazolo[4,3-c]quinolin-5-yl)-2-fluoropropylcarbamate (1-10) as a white solid. LRMS m/z (M+H) 519.2 found, 519.3 required.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.C[N:11]([C:13]([N:15]=NC(N(C)C)=O)=O)C.[C:22]1([N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:13]([NH:15][C:32](=[O:33])[CH2:31][CH2:30][C:29]([NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:34])#[N:11]
Reactant: O=C1CCC(=O)N1c1ccccc1
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: O=[N+]([O-])c1ccccc1
Product: N#CNC(=O)CCC(=O)Nc1ccccc1

Procedure:
Using high temperature NMR techniques (150° C., nitrobenzene), the rapid conversion of the diamide to N-phenylsuccinimide was observed.