Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C([O:9][C:10](=[O:24])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][C:20]#[CH:21])=[C:13]([F:22])[C:12]=1[F:23])C#C.O.[OH-].[Li+].Cl>O>[CH2:19]([O:18][C:14]1[C:15]([F:17])=[CH:16][C:11]([C:10]([OH:24])=[O:9])=[C:12]([F:23])[C:13]=1[F:22])[C:20]#[CH:21]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1c(F)cc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a mixed solution of 10 ml of THF and 10 ml of water, 6.5 g of the obtained 4-(2-propynyloxy)-2,3,5-trifluorobenzoic acid 2-propynyl ester and 2.0 g of lithium hydroxide monohydrate were added, followed by stirring at room temperature for 2 hours and further stirring at 50° C. for 2 hours. The reaction mixture obtained by concentration under reduced pressure until the entire volume was reduced to about half was acidified by adding hydrochloric acid and the obtained solid was collected by filtration. The solid was dried and washed with hexane, and 4.0 g of 4-(2-propynyloxy)-2,3,5-trifluorobenzoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]3[S:15][C:14]([CH:16]=O)=[CH:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([CH2:16][C:14]1[S:15][C:10]3[C:9]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:8][C:7]([N:6]4[C:5]5[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=5[N:3]=[C:2]4[CH3:1])=[N:12][C:11]=3[CH:13]=1)[CH2:33][CH2:32]2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(C=O)cc2n1
Reactant: Fc1ccc2c(c1)CCNC2
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCc4cc(F)ccc4C3)cc2n1

Procedure:
Following General Procedure L for reductive amination, 2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde and 6-fluoro-1,2,3,4-tetrahydroisoquinoline were reacted to give 221. LCMS m/z: 515.6 (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=O>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:21](=[O:23])[C:20]2[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=2)=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine (example 5, intermediate a) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the compound as a colorless solid (5%). MS (ESI+): m/z=460.064 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19]([CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])[CH3:17]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.8 %

Procedure:
To a stirred suspension of 2-chloro-5-(chloromethyl)pyridine (2.0 g, 12 mmol) in acetonitrile (60 mL) was added potassium carbonate (1.5 mL, 25 mmol) followed by 1-(ethoxycarbonylmethyl)piperazine (2.0 mL, 12 mmol). The resulting mixture was stirred at room temperature for 19 h. The mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give compound 348 (1.1 g, 30% yield) as a colorless liquid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.31 (1 H, d, J=2.0 Hz), 7.66 (1 H, d, J=6.1 Hz), 7.28 (1 H, d, J=8.1 Hz), 4.18 (2 H, q, J=7.1 Hz), 3.50 (2 H, br. s.), 3.21 (2 H, s), 2.36-2.77 (8 H, m), 1.27 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 298.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[CH:14]1([C:17]2[N:18]([CH:23]([CH3:25])[CH3:24])[CH:19]=[C:20](I)[N:21]=2)[CH2:16][CH2:15]1>>[CH:14]1([C:17]2[N:18]([CH:23]([CH3:25])[CH3:24])[CH:19]=[C:20]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:21]=2)[CH2:16][CH2:15]1
Reactant: CC(C)n1cc(I)nc1C1CC1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Product: Cc1cc(C#Cc2cn(C(C)C)c(C3CC3)n2)ccn1

Procedure:
The title compound, MS: m/e=266.3 (M+H+), was prepared in accordance with the general method of example A, step 2 from 2-methyl-4-trimethylsilanylethynyl-pyridine and 2-cyclopropyl-4-iodo-1-isopropyl-1H-imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:9][CH:10]=[O:11])[CH3:8])=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:9][CH:10]=[O:11])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(NC=O)c1ccncc1
Reactant: [H][H]
Solvent: CC(=O)O
Product: CC(NC=O)C1CCNCC1

Procedure:
N-(1-Pyridin-4-yl-ethyl)-formamide (1.86 g, 12.38 mmol) was dissolved in 50 ml of acetic acid. After addition of Rh (5% on Al2O3, 307 mg) the mixture was hydrogenated with 10 bar hydrogen and 100° C. for 120 hours. The mixture was evaporated and lyophilised. The crude material was used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][NH:10][CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][N:10]([CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])[C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
{2-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (70 mg, 0.15 mmol) and 4-chlorobenzoylchloride (81.0 mg, 0.463 mmol) in CHCl3 (20 mL) was treated with Et3N (20.8 mg, 0.385 mmol). The reaction mixture was stirred at 25° C. for 18 h then concentrated under vacuum. The residue was and purified by preparative HPLC using a YMC S10 ODS 30×100 mm column to afford the desired material (52.2 mg, 57%) as a white powder: 1H NMR (CD3OD, 400 MHz) δ 7.55 (s, 1H), 7.45 (m, 5H), 7.08 (m, 1H), 6.67 (m, 1H), 5.87 (m, 1H), 3.93 (m, 1H), 3.72 (m, 1H), 3.48 (m, 1H), 3.30 (s, 1H), 1.81 (m, 1H), 1.38 (s, 9H), 1.17 (m, 3H), 0.90 (m, 3H), 0.54 (m, 3H); LC/MS (ESI+) 592 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[Br:8][C:4]1[CH:5]=[CH:6][C:7]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]([F:1])[CH:3]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1ccc(Br)cc1F
Temperature: 90 °C
Yield: 17.9 %

Procedure:
A mixture of 3-fluorobromobenzene (5.0 g, 29 mmol) and aluminium (III) chloride (11.6 g, 87 mmol) was heated under argon until a slurry formed. Propionyl chloride (3.2 g, 35 mmol) was added over 15 min and the mixture was heated at 90° C. for 1 h. The reaction was poured onto ice-water (100 mL) and the resultant mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography (SiO2; heptane) to give the product (1.2 g, 18%) as a colourless oil: NMR δH (400 MHz, CDCl3) 1.18 (3H, t, J 7.5), 2.95 (2H, m), 7.29-7.38 (2H, m) and 7.75 (1H, t, J 8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[C:63]([F:65])[CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 42.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (150 mg, 0.21 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (91.69 mg, 0.24 mmol) in sodium carbonate (66.77 mg, 0.483 mmol), Pd(PPh3)2Cl2 (7.36 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 70 mg (41% yield) of titled compound. MS: m/z=778.0 (M+1).
Reaction SMILES: [CH3:1][Si](C[Li])(C)C.[CH2:7]([NH:14][C:15]([C:17]1([C:21]([O:23]CC)=O)[CH2:20][CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:21]([C:17]1([C:15]([NH:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:18][CH2:19][CH2:20]1)(=[O:23])[CH3:1]
Reactant: [Li]C[Si](C)(C)C
Reactant: CCOC(=O)C1(C(=O)NCc2ccccc2)CCC1
Solvent: C1CCOC1
Product: CC(=O)C1(C(=O)NCc2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
((Trimethylsilyl)methyl)lithium (1.0 M in pentane) (908 mL, 908 mmol) was added dropwise over 1 hr 20 min to a 0° C. solution of ethyl 1-(benzylcarbamoyl)cyclobutanecarboxylate (52.7 g, 202 mmol) in THF (703 mL) under N2. Stirring @ 0° C. was continued for 2 hrs during which time the solution became red. LC/MS after 1 hr looked the same as after 30 minutes, a complete reaction (m/e 232.1, M+H for desired product). While still @ 0° C., the reaction was quenched by the addition of anhydrous methanol (246 mL, over 45 minutes). There was solid formation which after ca. 30 minutes cleared up to form a turbid yellow solution. Note: methanol addition was dropwise; when further addition no longer caused extensive precipitation, the addition was accelerated to a slow stream. After 5 minutes, the ice bath was removed and stirring was continued for 30 minutes. Brine was added (800 mL), the layers were separated, the brine layer was extracted twice with EtOAc (300 mL each), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 50.19 g of a yellow solid. The crude product was stirred and sonicated for 30 minutes in 400 mL of hexane. The product was collected by filtration and rinsed with hexane to yield ca. 40 g of a yellow solid with some sticky lumps. The solid was sonicated again for several minutes in 400 mL of hexane, collected by filtration, rinsed with hexane, and dried under vacuum to yield 35.82 g of an off-white solid. The combined hexane filtrate was concentrated under vacuum to yield 8.67 g of a yellow oil, which by LC/MS contained desired product. Flash chromatography of the filtrate on silica gel (Teledyne-Isco RediSep Rf 80 g column), eluting with 250 mL of hexane, 400 mL of 80:20, and 400 mL of 40:60 hexane:EtOAc yielded 5.15 g of an off-white solid. The chromatographed solid was similar in purity to the triturated solid, and the two solids were combined to afford 40.97 g of the title compound as an off-white solid. LC/MS: m/e 232.1 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.48-7.17 (m, 5H), 5.78 (br. s., 1H), 4.44 (d, J=5.9 Hz, 2H), 2.62-2.46 (m, 4H), 2.16 (s, 3H), 2.01-1.88 (m, 1H), 1.88-1.75 (m, 1H).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.21 g of benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization and was thereupon again treated with active charcoal. The product separated upon renewed neutralization with concentrated hydrochloric acid. Recrystallization from 10 ml of 50% ethanol yeilded 0.06 g of N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(OC(C)C)(C)C>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[CH2:40][CH2:39]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Reactant: CN1CCNCC1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCOCCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (500 mg) and 1-methylpiperazine (5.0 ml) was stirred at 70° C. for 5.0 hours. Then diisopropyl ether (30 ml) was added to the reaction mixture. After the resultant precipitate was filtered off, the filtrate was evaporated. The residue was washed with water and dried to give (3RS)-1-[2-[2-(4-methyl-1-piperazinyl)ethoxy]ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.43 g).
Reaction SMILES: O1CCCC1.[CH:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32]Br>O>[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32][O:10][CH2:9][CH:6]1[CH2:8][CH2:7]1
Reactant: OCC1CC1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Br)c(COCC2CC2)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.92 g (13 mmol) of cyclopropylmethanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, the mixture was stirred at room temperature for 30 minutes, then, 10 ml of dehydrated tetrahydrofuran solution containing 0.56 g (1.3 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was further added to the mixture, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=2:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 157 mg of the title compound as a pale yellowish solid. (Yield: 29%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:15])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:23][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:34][CH:33]=3)[CH:31]=2)=O)=C(F)C(F)=C(F)C=1F>ClCCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:15][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:34][CH:33]=3)[CH:31]=2)=[O:23])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CO)C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCc1nnc(C(=O)NC2(CO)CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mmol, 0.21 g) in anhydrous DCE (2 mL), 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.5 mmol, 0.26 g) and TEA (0.5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with NaOH (0.5 M) solution, water, and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (7:3) to provide 3-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]2[CH2:22][N:19]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]3[CH:7]=[C:6]4[C:11](=[N:10][CH:9]=3)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]4)[CH2:20]2)[N:27]=1
Reactant: Cc1nc(C2CNC2)no1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C2CN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)C2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-azetidin-3-yl-5-methyl-1,2,4-oxadiazole hydrochloride (25 mg, 0.14 mmol; which may be prepared as described in Step 5), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (23 mg, 56%) as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]=1[C:34]1[CH:42]=[C:41]2[C:37]([C:38]([NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55])=[N:39][N:40]2COCC[Si](C)(C)C)=[CH:36][CH:35]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]=1[C:34]1[CH:42]=[C:41]2[C:37]([C:38]([NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55])=[N:39][NH:40]2)=[CH:36][CH:35]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Yield: 60.5 %

Procedure:
14.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.3 g of N-[6-[2-chloro-4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 50 cm3 of saturated sodium hydrogen carbonate solution and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.8 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried under reduced pressure (90 Pa; 45° C.) to give 600 mg of N-[6-[2-chloro-4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of white crystals.