Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[C:8]=2[Cl:16])=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:8]1[C:9]([C:13]([NH2:15])=[O:14])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][C:27]([C:24]2[C:23](=[O:30])[N:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:21]([CH3:20])[C:25]=2[CH3:26])=[O:28])=[CH:3][C:4]=1[F:19]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1nccc(Oc2ccc(N)cc2F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 14.5 h
Yield: 93.2 %

Procedure:
To a suspension of 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (306 mg, 1.40 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (390 mg, 1.68 mmol) in DCM (6 mL) was added EDCI (322 mg, 1.68 mmol) and HOAT (38 mg, 0.28 mmol). The mixture was stirred at 45° C. for 14.5 hours, then cooled to rt and quenched with 5 mL of water. The mixture was extracted with EtOAc (10 mL×3) and the combined organic phases were washed with brine (10 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/4) to give the title compound as a pale yellow solid (647 mg, 93.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn2c1COCC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 2a) (8.2 g, 42 mmol) in anhydrous dichloromethane (50 ml) was added trichloro-acetyl chloride (15.2 g, 84 mmol). The resulting mixture was stirred at room temperature for 3 days, and then evaporated to dryness. The crude product was purified by silica gel chromatography (eluting with 5 to 50% ethyl acetate in heptane) to give 11.3 g of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.36 min; m/z=340.08 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH:13]=[N:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[N:11]2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 90 °C
Yield: 77.9 %

Procedure:
To 3-(4-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (22.0 g, 65.8 mmol) in acetic acid (132 mL) and water (110 mL) was added iron powder. The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and filtered through Celite® followed by an ethyl acetate wash. The organic layer was separated and concentrated. Purification by flash column chromatography using 0-50% ethyl acetate/petroleum ether as eluent provided the title compound as a light yellow solid (15.6 g, 74%): 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=1.0 Hz, 1H), 7.68-6.92 (m, 6H), 6.29-5.93 (m, 2H), 3.27 (bs, 2H); ESIMS m/z 305 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolane-4-ylidene)-N-methoxy-acetamide (1.0 g, 2.8 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in MeOH (20 mL) was stirred at room temp for 1 h. The suspension was diluted with EtOAc and washed with 1N HCl followed by brine. The organic phase was dried (sodium sulfate) and concentrated. The title compound was purified by flash chromatography eluting with 100% hexane followed by 25% EtOAc/hexane to give a white solid (0.3107 g, 33% yield). 1HNMR (300 MHz, CDCl3) δ: 13.28 (1H, s), 7.41 (2H, m), 7.15 (1H, dd, J=9.52, 1.47 Hz), 6.45 (1H, s), 4.77 (2H, s), 3.89 (3H, s), 3.72 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([C:25]5[O:24][CH:28]=[CH:27][CH:26]=5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1ccco1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccco4)nc3cc21

Procedure:
Furan-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-furoyl chloride (87 μl, 0.87 mmol). The title compound was obtained as brown powder (147 mg, 45%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][CH2:12][OH:13])=[C:5]([CH3:14])[CH:4]=1>C(O)C.O=[Mn]=O>[OH:13][CH2:12][CH2:11][CH2:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[CH3:14]
Reactant: Cc1cc(CO)cc(C)c1CCCO
Agent: O=[Mn]=O
Solvent: CCO
Product: Cc1cc(C=O)cc(C)c1CCCO
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-hydroxymethyl-2,6-dimethyl-phenyl)-propan-1-ol (850 mg, 4.38 mmol) in ethanol (20 mL), MnO2 (1.14 g, 13.1 mmol) is added and the resulting suspension is stirred at 85° C. for 24 h. The mixture is filtered through celite and the solvent of the filtrate is evaporated. The product is purified by CC on silica gel eluting with DCM containing 3% of methanol to give 4-(3-hydroxy-propyl)-3,5-dimethyl-benzaldehyde as a pale yellow solid; LC-MS: tR=0.81 min; 1H NMR (CDCl3): δ 9.89 (s, 1H), 7.51 (s, 2H), 3.76 (t, J=5.8 Hz, 2H), 2.81-2.74 (m, 2H), 2.40 (s, 6H), 1.80-1.68 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[S:28]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=2)[N:14]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Product: O=S(=O)(Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1)c1cc(F)ccc1F

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,5-difluoro-benzenesulfonyl chloride (0.07 g) as a light yellow solid (0.086 g). MS (ESI−): 443.0 ([M−H]−)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC([O-])(C)C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:62][C:63]1[CH:68]=[CH:67][C:66]([NH:69][CH3:70])=[CH:65][CH:64]=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:62][C:63]1[CH:68]=[CH:67][C:66]([N:69]([CH3:70])[C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:65][CH:64]=1
Reactant: CNc1ccc(F)cc1
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ccc(F)cc2)cn1
Yield: 7.5 %

Procedure:
According to Scheme 22 Method B: To a mixture of 5-bromo-2-methoxypyridine (1 eq, 1.06 mmol, 0.14 mL), KOtBu (1.5 eq, 1.60 mmol, 0.18 g), Pd(OAc)2 (0.02 eq, 21 μmol, 48 mg), BINAP (0.04 eq, 42 μmol, 26 mg) in degassed DMF (1.5 mL) was added 4-fluoro-N-methylbenzenamine (1.2 eq, 1.28 mmol, 0.14 mL). The reaction mixture was microwaved at 130° C. for 5 min. The reaction mixture was quenched with water and the aqueous phase was extracted with AcOEt. The organic fraction washed brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 15 g SiO2, CH2Cl2/AcOEt 90/10) to afford N-(4-fluorophenyl)-6-methoxy-N-methylpyridin-3-amine (0.08 mmol, 20 mg, 8%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O)(=O)=O.C(Cl)[Cl:29]>CCOCC>[ClH:29].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCCl
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)c1ccc(C2=C(c3cccnc3)C(=O)CC2)cc1
Solvent: CCOCC
Product: Cl

Procedure:
To a solution of 3-(4-(methylsulfonyl)phenyl)-2-(3-pyridinyl)-2-cyclopenten-1-one (104 mg, 0.33 mmol) in CH2Cl2 (50 mL) was added methanesulfonic acid (0.02 mL, 0.32 mmol) and the solution was concentrated to give a foam. The foam was swished in Et2O to give 108 mg of the title compound as an off-white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[C:10]=1[O:18][CH3:19])[CH3:7])C.[OH-].[Na+]>S(=O)(=O)(O)O>[OH:3][CH:4]1[C:14]2[C:9](=[C:10]([O:18][CH3:19])[C:11]3[O:17][CH2:16][O:15][C:12]=3[CH:13]=2)[CH2:8][N:6]([CH3:7])[CH2:5]1
Reactant: CCOC(CN(C)Cc1ccc2c(c1OC)OCO2)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Temperature: 5 °C
Yield: 80.3 %

Procedure:
62.29 g (0.2 mol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde diethylacetal (3) was dissolved in 400 ml of 6N sulfuric acid and the solution was stirred under heating at 76°-78° C. for 1.5 hour. The solution was cooled and added with 25% aqueous solution of sodium hydroxide at a temperature below 30° C. to make the pH of the solution about 11. Then the solution was extracted with 200 ml and then with 100 ml of methylene chloride successively. The extracts were joined, washed with 100 ml of water and then dried over anhydrous mgnesium sulfate. The salt was filtered out and the magnesium was concentrated under reduced pressure. The residue was added with 120 ml of ethanol and dissolved by heating. Then, the solution was cooled to 5° C. to be crystalized. These crystals are filtered out, washed with 30 ml of cold ethanol and dried under a reduced pressure to obtain 38.09 g of 4-hydroxy- 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (m.p. 151°-153° C., yield: 80.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](NC1C=CC(C(O)=O)=CC=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(=O)O)ccc1N
Product: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting orange-brown solid was recrystallized from ethyl acetate and hexanes to provide the desired product (4.99 g) as tan prismatic crystals: m.p. 180-182° C.;
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH3:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(C)c(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: Cc1ccc(C)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (13.9 mg, 0.015 mmol, 3.0 mol % Pd), 2 [Example 1] (17.9 mg, 0.045 mmol, 4.5 mol %), and NaOt-Bu (140 mg, 1.4 mmol). The tube was purged with argon, fitted with a rubber septum and then DME (0.5 mL), 2-bromo-p-xylene (140 μL, 1.01 mmol) and morpholine (105 μL, 1.2 mmol) were added via syringe. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with ether (20 mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 185 mg (95%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH:41]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:47][S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), 4-dimethylaminopyridine (46 mg, 0.38 mmol), cyclopropane sulfonamide (91 mg, 0.75 mmol) in dichloromethane (3 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (37.8 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 504.1, observed: 504.2.
Reaction SMILES: [Br-:1].C(O[C:7]([N:9]([CH2:11][C:12]1([C:15]([NH:17][CH2:18][CH2:19][CH2:20][P+:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])[CH2:14][CH2:13]1)C)=O)(C)(C)C.Cl.C(OCC)C.N>C(Cl)Cl.CO>[Br-:1].[CH3:7][NH:9][CH2:11][C:12]1([C:15]([NH:17][CH2:18][CH2:19][CH2:20][P+:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: CN(CC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CNCC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.6 %

Procedure:
(3-{[(1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropyl)carbonyl]amino}-propyl)(triphenyl)phosphonium bromide (809 mg, 1.32 mmol) was dissolved in methylene chloride (4.0 mL) and methanol (0.4 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (1.7 mL, 3.44 mmol). The mixture was stirred overnight at room temperature. To the incomplete reaction was added additional 2.0 M hydrogen chloride in diethyl ether (0.36 mL, 0.71 mmol). After 3 additional hours, the reaction mixture was cooled with an ice bath and treated with 7N ammonia in methanol (0.77 mL, 5.42 mmol). After 30 minutes, the slurry that resulted was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (760 mg, 110%, 85% pure). The product of step 4 was used crude in next step.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c1
Temperature: 75 °C
Yield: 25.8 %

Procedure:
To a solution of 5-chloro-2-methyl-6-(3-methyl-benzyloxy)-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one from Example 4, Step E (25 mg, 0.06 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methyl propionamidine HCl (13 mg, 0.09 mmol) and potassium carbonate (25 mg, 0.18 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (7.6 mg, 26% yield). MS (M+H): 491; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.40 (s, 3H), 5.47-5.56 (m, 2H), 7.17 (s, 1H), 7.26-7.31 (m, 3H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=7.43 Hz, 1H), 8.76 (d, J=5.08 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.O=S(Cl)Cl.CN(C=O)C.[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:32])([CH3:31])[C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:31][C:25]1([CH3:32])[C:24]2[C:28](=[CH:29][C:21]([NH:20][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=3)=[CH:22][CH:23]=2)[NH:27][C:26]1=[O:30]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc3c(c2)NC(=O)C3(C)C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-methylisonicotinic acid (175 mg, 1.28 mmol) in dry toluene (12.8 ml) was added SOCl2 (167 mg, 103 μl, 1.4 mmol) and dry DMF (9.33 mg, 9.89 μl, 128 μmol) under an argon atmosphere. The mixture was heated under reflux for 2 hours and the solvent was evaporated under reduced pressure. The residue was suspended in dry dichloromethane (3.51 ml) and a suspension of 6-amino-3,3-dimethylindolin-2-one (0.15 g, 851 μmol) and DIPEA (330 mg, 446 μl, 2.55 mmol) in dry dichloromethane (5 ml) was added portionwise. The suspension was stirred under an argon atmosphere at room temperature for 16 hours, then diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as brown solid (99 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](O)([CH3:10])[C:6]=2[CH:12]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC1(O)COc2cc(N3CCCCC3)c(Cl)cc21
Solvent: CC(=O)O
Product: Cc1coc2cc(N3CCCCC3)c(Cl)cc12

Procedure:
A solution of 1.4 g (5.2 mmole) of 5-chloro-3-hydroxy-3-methyl-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in 20 ml of acetic acid/5N hydrochloric acid 1:1 is maintained at 85° for one hour. The reaction mixture is concentrated in a vacuum rotary evaporator, water is added to the residue and the whole is adjusted to pH 7 with saturated sodium carbonate solution and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel using chloroform as eluant yields 5-chloro-3-methyl-6-(piperidin-1-yl)-benzofuran which, after recrystallisation from petroleum ether, melts at 82°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][CH2:14]/[C:13](=[CH:17]\N(C)C)/[C:12]2=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[C:12]3[N:47]=[C:45]([NH:44][C:34]4[CH:35]=[CH:36][C:37]([N:38]5[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]5)=[C:32]([O:31][CH3:30])[CH:33]=4)[N:46]=[CH:17][C:13]=3[CH2:14][CH2:15][CH2:16]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(S(=O)(=O)c2cccc(Cl)c2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(S(=O)(=O)c2cccc(Cl)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-(3-chloro-benzenesulfonyl)-6-[1-dimethylamino-meth-(E)-ylidene]-cyclohexanone (108 mg, 0.33 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (46 mg, 30%). MS ISP (m/e): 510.3/512.2 (100/39) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.59 (s, 1H), 8.39 (s, 1H), 7.66-7.70 (m, 3H), 7.58 (d, 1H), 7.47-7.52 (m, 2H), 7.02-7.04 (m, 2H), 6.96 (d, 1H), 4.89 (m, 1H), 3.68 (s, 3H), 2.51-2.65 (m, 2H), 2.16 (s, 3H), 2.00-2.16 (m, 3H), 1.76 (m, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Br:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Br:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH2:24][OH:25]
Reactant: O=C(CO)CBr
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Solvent: C1CCOC1
Product: OCC(CBr)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-bromo-3-hydroxypropanone under nitrogen to give 2-[[2-bromo-1-(hydroxymethyl)ethylidene]-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.