Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:7]([N:19]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCN1CCCC1=O
Yield: 80.5 %

Procedure:
Following example 5, 18.8 g (0.22 M) of γ-butyrolactone and 37 g (0.2 M) of n-dodecylamine was heated for 24 hours. Distillation of the residue gave 40.7 g (80.3%) of 1-n-Dodecylazacyclopentan-2-one; b.p. 165°-170°/0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].[K+].[Br-].SCC(CO)O>C(O)C.CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)c1csc(N)n1
Agent: OCC(O)CS
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1nc(/C(=N/OCc2c(Cl)cccc2Cl)C(=O)O)cs1
Yield: 42.8 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(2,6-dichlorobenzyloxyimino)acetate (4.8 g) was hydrolysed with aqueous sodium hydroxide (1N, 25.6 ml) in ethanol (40 ml), acetone (20 ml) as described in Example 4e to give the title compound (1.9 g), νmax (KBr) 3123 (br), 1610 (br), and 992 cm-1, δH [(CD3)2SO]5.32 (2H, s), 6.81 (1H, s), 7.17 (2H, br s), and 7.44 (3H, m), [Mass spectrum: +ve ion (thioglycerol) MH+ (346)].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[OH:21][C@@H:20]1[C@H:19]([OH:23])[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]3[CH:47]=[CH:46][N:50]=[CH:49]3)=[O:52])[CH2:3]1)=[N:8][C:9]=2[NH:31][CH2:32][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (Intermediate M) (0.24 g, 394 μmol) and CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by chromatography on silica eluting with 100% DCM changing to 5% MeOH in DCM to afford the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:18])[C:8](=[O:11])[CH2:7]2
Reactant: COS(=O)(=O)OC
Reactant: O=C1Cc2cccc(F)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1C(=O)Cc2cccc(F)c21
Temperature: 100 °C

Procedure:
This is similar to the procedure described in G. W. Rewcastle, B. D. Palmer, E. M. Dobrusin, D. W. Fry, A. J. Kracker and W. A. Deny, Journal of Medicinal Chemistry, 1994, 37, 2033-2042. A suspension of the 7-fluoro-1,3-dihydro-indol-2-one (9, 1.0 g, 6.62 mmol.) in H2O (30 mL) and NaOH (0.397 g, 9.92 mmol., 1.50 eq.) was treated with dimethyl sulfate (1.24 g, 9.86 mmol., 1.49 eq., 0.933 mL; added all at once) and heated to 100° C. for approx. 10 min. and then allowed to cooled to about 50° C. An additional 1.0 eq. of NaOH (0.265 g) and then additional 1 eq. of dimethyl sulfate (0.835 g, 0.626 mL) were added. Again heated to 100° for approx. 10 min. Then cooled to 0° C. in an ice bath and stirred and then filtered off solids, washed several times with water and dried on buchner funnel under vacuum overnight to yield the title compound as a solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.4 (d, J=2.5 Hz, 3H) 3.5 (s, 2H) 6.9 (m, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12])[CH3:6]>ClCCCl>[CH2:17]([O:16][C:15]1[C:8]([O:7][CH2:5][CH3:6])=[CH:9][C:10]([CH:11]=[O:12])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[CH3:18]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCC
Temperature: 0 °C

Procedure:
2.13 ml of fuming nitric acid were added within 30 minutes to a solution, cooled to −30° C. of 10 g of 3,4-diethoxybenzaldehyde in 185 ml of 1,2-dichloroethane. Subsequently, the reaction mixture was left to warm to 0° C. and was poured on to ice. The product was isolated by extraction. There were obtained 12.06 g of 4,5-diethoxy-2-nitro-benzaldehyde.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
500 mg of 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 50 ml of MeOH:water/3:1. 1 g of lithium hydroxide monohydrate was added to the added to the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: [CH:1]1([C:6]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:10][CH2:9][CH:8]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: O=CCC(C(=O)C1CCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCC2)c2ccccc2)CC1
Yield: 66.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol) and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodium triacetoxyboranehydride (1.77 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine (370 mg) in 67% yield. The di-hydrochloric acid salt was prepared as described above.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:35]1[CH2:40][CH2:39][O:38][C:36]1=[O:37]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:35]2[CH2:40][CH2:39][O:38][C:36]2=[O:37])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: O=C1OCCC1O
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC4CCOC4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and α-hydroxy-γ-butyrolactone were processed as described in Example 62A to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14][NH2:15]>O>[NH2:13][C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][CH3:14])[CH:7]=2)=[N:9][N:10]=1
Reactant: Nc1nnc(-c2ccnc(Cl)c2)s1
Reactant: CN
Solvent: O
Product: CNc1cc(-c2nnc(N)s2)ccn1
Temperature: 130 °C
Yield: 47 %

Procedure:
To 5-(2-chloropyridin-4-yl)-1,3,4-thiadiazol-2-amine 8.1.C (1.03 g, 4843 μmol) in a pressure tube was added 16 mL of methylamine 40% in water. The reaction was heated at 130° C. for 3 hours. The pressure tube was cooled down and precipitates were generated. The precipitates were filtered and rinsed with water and dried to afford 476 mg of product 8.1.D (47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:16](=O)[NH2:17])[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:16]#[N:17])[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CC1CC1(C#N)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of (1-carbamoyl-2-isobutyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (5.8 g, 21.5 mmol) in dry DMF (100 mL) was added cyanuric chloride (5.5 g, 30.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and was poured into cold 0.5N NaOH (200 mL). The aqueous phase was extracted with EtOAc (2×150 mL) and the combined organic layer was washed with water and brine and dried over Na2SO4. Removal of excess of solvent, followed by purification of the residue by flash column chromatography using hexanes/EtOAc (9:1) as eluent gave 4.9 g (91%) of (1-cyano-2-isobutyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless foam: 1H NMR (300 MHz, CDCl3) δ 0.86 (m, 1H), 0.94 (d, J=4.0 Hz, 3H), 0.96 (d, J=4.0 Hz, 3H), 1.56 (m, 1H), 1.37-1.56 (m, 12H), 1.71 (m, 1H), 3.32 (d, J=6.1 Hz, 2H), 5.26 (s, 1H); 13C (75 MHz, CDCl3) δ 14.5, 18.8, 21.9, 22.2, 24.4, 28.0, 28.1, 36.3, 40.4, 79.3, 122.9, 155.4; MS (APCI) m/z 253 [M+H]+.
Reaction SMILES: C(Cl)CCl.[CH3:5][NH:6][CH3:7].[Cl:8][C:9]1[N:14]=[C:13]([C:15](O)=[O:16])[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl>[Cl:8][C:9]1[N:14]=[C:13]([C:15]([N:6]([CH3:7])[CH3:5])=[O:16])[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C(O)c1nc(Cl)ccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)c1nc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
EDC (650 mg, 3.39 mmol) and dimethylamine (2.0 M solution in THF, 2.30 mL, 4.60 mmol) were added at room temperature to a solution of 6-chloro-3-(trifluoromethyl)pyridine-2-carboxylic acid (516 mg, 2.29 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-70/30 (gradient)] to obtain the title compound (246 mg, yield: 43%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:5].[Cl:21][CH2:22][CH:23]1[O:25][CH2:24]1.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:6]=1[C:4]1([C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[O:25][CH:23]([CH2:22][Cl:21])[CH2:24][O:5]1
Reactant: COC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: ClCC1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1C1(c2ccccc2F)OCC(CCl)O1
Reaction time: 0.5 h

Procedure:
To a solution of 47 g (0.16 mol) of the end product of Example 6 in 350 ml of dry toluene was added 21.4 ml (0.18 mol) of stannic chloride, and after 5 hrs a solution of 24 ml (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene was added with stirring over a 30 min period. After 18 hrs an additional 12 ml (0.154 mol) of 1-chloro-2,3-epoxypropane was added over a 15 min period. After 4 hrs the reaction was cooled in an ice bath and made basic with concentrated ammonium hydroxide. The reaction was filtered through celite, and the celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of alumina. The column was eluted with 4 l of dichloromethane/petrol (2/l) to give an oil, which was about 90-95% pure by TLC. A sample was crystallized and recrystallized from ether/petrol to give white prisms, mp 117°-122° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([O-:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[K+].N[C@H](C(O)=O)CCSC.[K].C(=O)=O>>[NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCC(N)C(=O)[O-]
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C=O
Agent: [K+]
Product: CSCCC(N)C(=O)O

Procedure:
686 l per hour of an aqueous solution with 83.6 kg of potassium D,L-methioninate (hydrolysis solution of 5-(2-methylmercaptoethyl)-hydantoin) with additionally 39.77 kg of recycled methionine and potassium compounds are fed in continuously at the top of a stirred reactor 10 with a capacity of 340 l. At the same time, carbon dioxide is fed in at the bottom of the reactor so that a pressure of 2-3 bar is carried in the reactor. Similarly, 0.38 kg per hour of defoaming agent are fed into the reactor in the form of an aqueous emulsion; this quantity corresponds to approximately 3940 ppm of defoaming agent per kilogram of total methionine. The reaction temperature is kept at 25° C. In order to keep a constant level in the reactor, quantities of reaction solution corresponding to the inflow are removed from the lower part of the reactor. The suspension removed is filtered, 66.5 kg per hour of solid D,L-methionine (calculated as dry substance) being obtained, and the mother liquor with a residual content of 39.77 kg of D,L-methionine can be recycled to the hydantoin hydrolysis stage as saponification agent. The yield is quantitative.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH:9]=[O:8])[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC1=C(C)CCC(CC=O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The deprotected alcohol was oxidized by the standard “Swern” procedure (Mancuso, Synthesis 1981 p 165, incorporated herein by reference) as follows: The alcohol (5 mmol) was added to a solution of oxalyl chloride (3.5 mL, 7.0 mmol) in CH2Cl2 (30 mL) with DMSO (0.64 mL, 9.0 mmol) at −78° C. After 40 min., NEt3 (2.50 mL) was added and the mixture was warmed to rt. After standard aqueous work-up and purification, (3-ethyl-4-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate K5) was isolated (˜90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].C(Cl)Cl.CO.O1CCOCC1>[Br:21][C:19]1[CH:20]=[C:15]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[CH:12][N:11]=2)[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCCC1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
Following Example 142a, 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (500 mg, 2 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (0.54 g, 2 mmol), cesium carbonate (1.9 g, 6 mmol), tris(dibenzylidene-acetone)dipalladium(0) (0.18 g, 0.2 mmol), Xantphos (0.23 g, 0.4 mmol) and 1,4-dioxane (20 mL) were heated at 100° C. for 8 hours. Work-up and flash column chromatography (silica, 9:1 methylene chloride/methanol) give a 82% yield (0.6 g) of 5-bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one 202a as a green solid: MS (ESI+) m/z 365.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)OC(C)(C)C)=[N:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:30][CH:31]([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CN(C=O)C>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([O:32][CH:31]([F:30])[F:40])=[CH:34][CH:35]=3)[C:3]2=[O:29])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(CN2C(=O)C(Nc3ccc(OC(F)F)cc3)=C(c3ccccc3)C2=O)cn1
Temperature: 150 °C
Yield: 53.9 %

Procedure:
A mixture of tert-butyl {5-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]pyridin-2-yl}carbamate ( 0.70 g, 1.7 mmol) and 4-(difluoromethoxy)-aniline (0.54 g, 3.4 mmol) in DMF (4 mL) was heated in a microwave reactor at 150° C. for eight min. The solvent was evaporated and the residue was purified on a column (Isolute® SI, 10 g/70 mL), using CH2Cl2 and then CH3OH/CH2Cl2 (1:99, 2:98 and then 5:95) as eluant, to give 0.4 g (54%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.99 (bs, 1H), 7.67-7.62 (m, 2H), 7.14-7.04 (m, 3H), 6.91 (d, J=8 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 6.72 (d, J=9 Hz, 2H), 6.63 (d, J=9 Hz, 2H), 6.33 (t, J=74 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.CCOCC.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccc(Cl)nc2)cc1

Procedure:
Two grams (7.6 mmol) of 2-chloro-5-(4-nitrophenoxy) methylpyridine and 4 grams (76.0 mmol) of ammonium chloride in 40 ml of ethanol and 20 ml of water are heated to 60°, after which 2.1 grams (38.0 mmol) of iron powder is added in small portions over 15 minutes. The mixture is heated under reflux for 2 hours. The reaction is cooled and stripped, and the residue is taken up in ether, washed with water, dried over sodium sulfate and stripped to yield 2-chloro-5-(4-aminophenoxy)methylpyridine.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2[CH:34]=[CH:33][C:32](CC(C)C)=[CH:31][CH:30]=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)C(C)C.C(OC(=O)C(C)(C1C=CC=CC=1)CCCCC(=O)CCCCC(C)(C1C=CC=CC=1)C(OCC)=O)C.[OH-].[K+]>C(O)C.O>[CH3:28][C:24]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:39])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:40])([C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[C:25]([OH:27])=[O:26]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCCC(=O)CCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
According to the procedure given for 210f, 209d (3.93 g, 7.9 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL) and water (10 mL) at reflux for 3 h and at room temperature overnight. After the usual workup and drying, 210d (3.0 g, 87%) was obtained as an oil 1H NMR (CDCl3): δ 7.40-7.10 (m, 10H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4H), 1.60-1.45 (m, 4H), 1.54 (s, 6H), 1.25-1.10 (m, 4H). 13C NMR (CDCl3): δ 211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba): Calcd for C27H35O5 (MH+): 439.2484. found: 439.2497. HPLC: 93.7% pure.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH:24]=[CH:25][CH:26]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>C(#N)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:40][CH2:41][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:22]=1
Reactant: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)c1
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)c1
Yield: 77.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2′-methyl-1,1′-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step C (0.600 g, 1.1 mmol) and dimethyl sulfoxide (0.41 mL, 5.8 mmol) in dry acetonitrile (5.5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.23 mL, 2.2 mmol) and the reaction mixture heated to reflux for 45 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (25 mL), washed with 1 M sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale orange foam. Purification by flash chromatography using ethyl acetate as solvent afforded a pale yellow foam that was recrystallized from ethyl acetate/diethyl ether/hexane to give the title compound (0.435 g, 74%) as an off-white crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])OCCC)#[N:2].[NH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:19]([N:18]1[C:1](=[NH:2])[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[N:8]=[C:9]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CCCOC(=Nc1sccc1C#N)OCCC
Product: CCCOc1nc2sccc2c(=N)n1CCC

Procedure:
In a sulfonation flask, 5.7 g (0.023 mol) 3-cyano-2-(1,1-dipropoxymethylenamino)thiophene and 35 ml 1-aminopropane are heated at reflux temperature for 5 hours. Then the excess of 1-aminopropane is distilled off and the residue purified by column chromatography over silica gel (eluant: hexane/ethylacetate 1:1). Yield: 5.1 g of 3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylideneamine in the form of brownish crystals; m.p. 61-63° C.