Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:10]1[C:18]2[CH:17]=[C:16](B(O)O)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([OH:9])=[O:8].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([F:30])=[CH:25][N:24]=1.Cl>COCCOC.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>[Cl:22][C:23]1[N:28]=[C:27]([C:16]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:7]([OH:9])=[O:8])[C:18]=3[CH:17]=2)[C:26]([F:30])=[CH:25][N:24]=1
Reactant: O=C(O)c1cccc2sc(B(O)O)cc12
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3F)cc12
Temperature: 100 °C
Yield: 53.1 %

Procedure:
An aqueous 2N Na2CO3 solution (36 mL) is added dropwise to a stirred solution of (4-carboxybenzo[b]thiophen-2-yl)boronic acid (3.63 g, 18.8 mmol) and 2,4-dichloro-5-fluoropyrimidine (3.00 g, 18.0 mmol) in ethyleneglycol dimethyl ether (50 mL) at room temperature under nitrogen atmosphere. Upon the completion of addition, dichlorobis(triphenylphosphine)palladium(II) (0.22 g, 3% mol) is added in one portion, then the reaction mixture is heated at 100° C. overnight. The mixture is cooled to 10° C., then 37% HCl (10 mL) is added in portions to form a suspension. After filtration and washing with water, the solid is dried under vacuum. The dry solid is suspended in 30 mL of dichloromethane/ethanol (10:1), sonicated, filtered, and dried again to provide 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (2.95 g, 48% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[O:24][C:25]([C:28](OCC)=[O:29])=[CH:26][CH:27]=2)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[O:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=2)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.06 g (54.6 mmol) of lithium aluminum hydride were initially charged in 250 ml of absolute THF, and a solution of 18.8 g (54.6 mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole in 250 ml of THF was added dropwise. After 45 min the mixture was admixed with 25% strength potassium carbonate solution and stirred at RT for 30 min and the precipitate was filtered off with suction and washed with THF. The combined organic phases were concentrated using a rotary evaporator and the residue was recrystallized from isopropanol. This gave 11.0 g (67%) of the title compound. m.p.: 113-114° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22]Cl)=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>>[F:40][C:26]([F:25])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][C:4]([C:6]3[CH:19]=[CH:18][C:17]4[O:16][C:15]5[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22][N:36]6[CH2:35][CH2:34][N:33]([C:29]7[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:39])([F:40])[F:25])[CH:28]=7)[CH2:38][CH2:37]6)=[CH:13][CH:14]=5)[CH2:9][C:8]=4[CH:7]=3)=[O:5])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc1O2

Procedure:
Prepared from compound 17 and 4-(3-trifluoromethyl-phenyl)-piperazine according to General Procedure C to give a solid. Mp 155-157° C. 1H NMR (CDCl3, 400 MHz) δ7.92-7.88 (m, 4H), 7.39 (t, J=8.8 Hz, 2H), 7.17-7.13 (m, 6H), 7.07 (dd, J=8.8, 2.0 Hz, 2H), 4.17 (s, 2H), 3.53-3.04 (m, 24H). Anal. (C41H40F6N4O3).
Reaction SMILES: Br.[CH3:2][NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=O)[CH2:8]Br.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>C(O)C>[NH:17]([C:18]1[S:19][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([NH:3][CH3:2])[CH:5]=2)[N:20]=1)[C:14]([NH2:16])=[NH:15]
Reactant: N=C(N)NC(N)=S
Reactant: CNc1cccc(C(=O)CBr)c1
Agent: Br
Solvent: CCO
Product: CNc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 20 gm of 3-methylamino phenacyl bromide hydrobromide, 7.65 gm of amidinothiourea and 100 ml of ethanol was refluxed for 4 hours, and then cooled to room temperature. The dihydrobromide which separated out was filtered off, dissolved in water, and the solution was made alkaline with 10% sodium hydroxide. The free base was collected and dried, yielding 11.5 gm of the title compound, m.p. 198°-200° C.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:20])=[C:17]([F:27])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
A mixture of 4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (20 mg, 0.05 mmol), EDCI (21 mg, 0.10 mmol), DMAP (12 mg, 0.10 mmol) and methanesulfonamide (9 mg, 0.10 mmol) in DCM (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with DCM (10 mL) and washed with HCl (2 N, 15 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (20%-30% CH3CN in 0.1% NH4HCO3) to give target compound (4 mg, 17%) as a pale yellow solid. LCMS (ESI) Method A: RT=3.86 min, m/z: 446.5 [M+H]+. 1H-NMR (500 MHz, MeOH-d4,): δ 7.67-7.31 (m, 5H), 7.30 (d, J=8.5 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 4.65-3.62 (m, 1H), 4.61-4.22 (m, 5H), 3.36 (s, 3H), 3.25-3.23 (m, 1H), 1.99-1.95 (m, 1H), 0.94-0.61 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[C:8]([F:14])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].O.N1C=C[CH:26]=[CH:25][CH:24]=1.CC(B1OB(C(C)=C)OB(C(C)=C)O1)=C>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>[F:14][C:8]1[C:9]([O:12][CH3:13])=[N:10][C:11]2[C:6]([CH:7]=1)=[N:5][CH:4]=[C:3]([F:15])[C:2]=2[C:25]([CH3:26])=[CH2:24]
Reactant: c1ccncc1
Reactant: COc1nc2c(Br)c(F)cnc2cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(C)B1OB(C(=C)C)OB(C(=C)C)O1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: C=C(C)c1c(F)cnc2cc(F)c(OC)nc12

Procedure:
A solution of 8-bromo-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine (1.14 g, 4.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) in degassed dimethoxyethane (40 ml) was stirred under argon for 30 minutes. Potassium carbonate (570 mg, 4.2 mmol), water (12 ml) and pyridine-tris(1-methylethenyl)boroxin (1:1) (470 mg, 1.66 mmol) were added the mixture was heated to reflux for 5 hours. The cooled mixture was treated with water (100 ml) and ether (200 ml). The phases were separated and the aqueous phase further extracted with ether (2×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica eluting with a gradient of 0-50% ethyl acetate in hexane affording a white solid (820 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[O:22][C:21]2=[O:28].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:23]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=4)[C:5]([CH3:16])([CH3:15])[C:6]=3[CH:7]=2)=[O:27])=[C:20]([CH:19]=1)[C:21]([OH:28])=[O:22]
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (25.0 g, 0.092 mol) and 5-bromoisobenzofuran-1,3-dione (26.89 g, 0.119 mol) were placed in a reaction vessel, and added with dichloromethane (700 ml). At 0° C., aluminum chloride (18.5 g, 0.138 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 5-bromo-2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (27.9 g, yield 61%) was obtained.
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[C:10]([O:14]C)[CH:11]=2)[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.N1C=CC=CC=1>O>[S:1]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: COc1cnc2cc(S(N)(=O)=O)sc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NS(=O)(=O)c1cc2ncc(O)cc2s1
Temperature: 190 °C
Yield: 68 %

Procedure:
A mixture of 2-sulfamoyl-6-methoxythieno[3,2-b]pyridine (512 mg, 2.1 mmol) and pyridine hydrochloride (1.62 g, 14 mmol), under a nitrogen atmosphere, was placed in an oil bath heated at 190° C. for 3/4 hour. The cooled mixture was diluted with water as the product slowly crystallized out. The mixture was extracted into ethyl acetate/methanol, washed with water, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated. The residue was triturated with diethyl ether and the product was collected by filtration (330 mg, 68% yield). Crystallization from hot ethyl acetate/methanol by boiling off the methanol gave pure product, m.p. 248°-250° C.
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([F:23])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:25].[Na+].CO>C(OCC)(=O)C>[F:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([C:11](=[O:12])[CH:2]([OH:25])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)c2ccccc12
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluoro-1-naphthyl)-6-oxohexanoate (34.3 g), sodium formate (34.0 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (19.0 g, 65%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH2:19][CH3:20])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:21][CH3:22])[C:6]1=[O:23])=[O:4].[NH2:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:31]1([NH:30][C:28]([C:27]2[CH:26]=[C:25]([NH:24][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH2:19][CH3:20])[CH:12]=4)[N:7]([CH2:21][CH3:22])[C:6]3=[O:23])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(CC)OCCO3)ccc21
Product: CCC(=O)c1ccc2c(c1)C(C(=O)Nc1cccc(C(=O)Nc3ccccc3)c1)C(=O)N2CC

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-ethyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-phenyl-benzamide. Purified by flash-chromatography (chloroform/methanol, 20:1) followed by trituration in hexanes/ethyl acetate. mp 179-180° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8]([NH:15][CH2:16][CH2:17][C:18](O)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[C:11]([O:10][C:8]([NH:15][CH2:16][CH2:17][C:18]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[O:19])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)NC(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC(C)N(C(=O)CCNC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 140.2 %

Procedure:
To a mixture of diisopropylamine (280 μl; 1.99 mmol; 1 eq) and boc-beta-alanine (414.7 mg; 2.19 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (829 μl; 5.98 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1 527 mg; 5.98 mmol; 3 eq). The mixture is stirred for 2 days at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layers are dried over Na2SO4, filtered and concentrated to give 760 mg of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title compound is isolated as a slightly yellow solid (511.2 mg; 94%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[C:3]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(CC(=O)O)C1=O

Procedure:
4.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid, 80 ml of absolute tetrahydrofuran and 5 ml of acetyl chloride are boiled at reflux for 4 hours while stirring. Thereafter, the mixture is evaporated. The residue is filtered through silica gel (granular size 0.2-0.5 mm). The evaporation residue of the fractions which are eluted with ethyl acetate is stirred in diethyl ether. By filtration there is isolated (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid of melting point 95°-96°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][N:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][N+:14]=1[O-:6]
Reactant: COc1cnc(Cl)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(C)c(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloroperoxybenzoic acid (70%, 695 mg, 2.82 mmol) was added to a solution of 2-chloro-5-methoxy-3-methylpyridine (370 mg, 2.35 mmol) in dichloromethane (10 mL). After stirring for 18 hours at room temperature, the reaction mixture was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) to afford the product as a white solid. Yield: 370 mg, 2.13 mmol, 91%. 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J=2.5 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CO>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([CH2:23][NH2:24])=[CH:21][CH:22]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C#N)nc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)nc1
Reaction time: 3.5 h
Yield: 87.2 %

Procedure:
In a flask, 2920 mg (8.72 mmol) {2-[(6-Cyano-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester and 1000 mg Pd (10% on carbon) were placed under nitrogen and 10 ml THF and 120 ml methanol were added. The starting material was hydrogenated under atmospheric pressure and at rt for 3.5 h. The catalyst was filtered off. The solvent was evaporated and the residue was subjected to silica gel chromatography (toluene/isopropanol/NH3 (conc.) 16:20:1) to yield 2600 mg (7.6 mmol) {2-[(6-Aminomethyl-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; exact MW [M+H] calc'd: 343.18; MW found [M+H]: 343.2.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:12]1([CH2:18][S:19]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([NH2:29])=O)(=[O:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(#N)C.O>[C:12]1([CH2:18][S:19]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]#[N:29])(=[O:20])=[O:21])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
To a solution of 0.67 ml DMF (8.7 mmol)in 10 ml acetonitrile at 0° C. was added 0.70 ml (8.0 mmol) oxalyl chloride. A white precipitate was formed immediately and was accompanied by gas evolution. When complete, a solution of 2.0 g (7.5 mmol) of (2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinecarboxamide in 5.0 ml acetonitrile was added. When the mixture became homogeneous, 1.35 ml (16.5 mmol) pyridine was added. After 5 min., the mixture was diluted with water, and extracted by 200 ml ethyl acetate. The organic layer was concentrated and further purified by silica gel to give 1.5 g product as a white solid (80% yield). 1H NMR (CDCl3): d 01.92 (m, 2H); 2.01 (m, 1H); 2.11 (m, 1H); 3.45 (m, 2H); 4.35 (s, 2H); 4.65 (m, 1H); 7.26–7.45 (m, 5H, aromatic).
Reaction SMILES: [BH4-].[Na+].O[CH:4]([C@H:9]1[C:11]([CH3:13])([CH3:12])[C@H:10]1[C:14]([OH:16])=[O:15])[C:5]([Cl:8])([Cl:7])Cl.Cl>CN(C)C=O.O>[Cl:8][CH:5]([Cl:7])[CH:4]1[CH:9]2[CH:10]([C:11]2([CH3:12])[CH3:13])[C:14](=[O:15])[O:16]1
Reactant: CC1(C)[C@H](C(O)C(Cl)(Cl)Cl)[C@@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2C(=O)OC(C(Cl)Cl)C21
Temperature: 80 °C
Yield: 25 %

Procedure:
Sodium borohydride (0.12 mmol) was added to a solution of cis 2-(1-hydroxy-2,2,2-trichloroethyl)-3,3-dimethycyclopropane carboxylic acid (0.12 mol) in dry dimethylformamide (0.4 ml), and the mixture was heated for 30 minutes at 80° C. An additional amount of 0.12 mmol sodium borohydride was then added and the mixture was heated for a further 15 minutes at 80° C. It was then diluted with water, acidified with concentrated HCl and extracted with deuterochloroform, CDCl3. The extract was washed with water and analysed by NMR, which showed a yield of 25% of the desired product, with 30% of unconverted starting material.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Reactant: COc1ccc(B(O)O)cc1
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)cc1
Yield: 47 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 4-methoxyphenyl boronic acid. The title compound (90 mg) was obtained as a yellow solid, (yield=47%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[NH:20])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.CN(C)/[CH:24]=[C:25](\[F:37])/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>COCCO>[CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:21]=[C:26]([C:28]4[N:32]([CH:33]([CH3:34])[CH3:35])[C:31]([CH3:36])=[N:30][CH:29]=4)[C:25]([F:37])=[CH:24][N:20]=3)=[CH:16][CH:17]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Solvent: COCCO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCC[C@@H]4C(=O)NC4CC4)cc3)ncc2F)n1C(C)C
Temperature: 200 °C
Yield: 61.6 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 63) (0.36 g, 1.25 mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 0.15 g, 0.63 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (180 mg, 62%). NMR (400.132 MHz, CDCl3) 8.21 (d, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 6.80 (s, 1H), 6.59 (m, 3H), 5.55 (septet, 1H), 3.62 (t, 1H), 3.21-3.15 (m, 1H), 2.74-2.68 (m, 1H), 2.58 (s, 3H), 2.28-2.22 (m, 2H), 2.05-1.98 (m, 1H), 1.96-1.86 (m, 1H), 1.45 (d, 6H), 0.79-0.72 (m, 2H), 0.44-0.37 (m, 2H); m/z 464.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-].OS([O-])(=O)=O.[K+].C([O-])(O)=O.[Na+]>>[Cl:31][C:26]1[CH:25]=[C:24]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[N:16]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][N:7]3[CH2:14][CH2:13][C:10]4([CH2:12][CH2:11]4)[C@H:9]([OH:15])[CH2:8]3)[CH2:17][CH2:18]2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Product: O=C1CCN(c2ccc(Cl)c(Cl)c2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Temperature: 0 °C
Reaction time: 22 h
Yield: 75.2 %

Procedure:
A solution of 0.180 g (0.37 mmol) of (S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyric acid methyl ester in 4 ml of ETOH was treated at 0° C. with 0.017 g (0.74 mmol) of LiBH4. The reaction was stirred 10 min at 0° C. and 22 h at RT, cooled (0° C.) and treated with 0.009 g (0.37 mmol) of LiBH4 and after 5 h again cooled (0° C.) and treated with 0.009 g (0.37 mmol) of LiBH4. After 1 h at RT, the reaction was cooled (0° C.), acidified with 10% aq. KHSO4 solution and then basified with sat. aq NaHCO3 solution and extracted with EtOAc (3×). The organic phases were washed with aq. 10% NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2:MeOH 95:5 to 9:1) to yield 0.127 g (75%) of the title compound as white foam. MS: 456.2 (MH+, 2Cl).