Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.Cl.[F:16][C:17]1[CH:18]=[C:19]([C@@H:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[NH2:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C@@H:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[NH:29][C:9](=[O:11])[C:6]2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[CH:8][N:7]=2)[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]
Reactant: COc1cnc(C(=O)O)cc1[N+](=O)[O-]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-methoxy-4-nitropicolinic acid (1 g, 0.005 mol) in DMF (10 mL) were added (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g, 0.0075 mol, molekula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich). The reaction mixture was stirred for 12 h at rt. The reaction progress was monitored by TLC (50% EtOAc in pet ether). After completion of reaction, water (10 mL) was added and product was extracted with EtOAc (50 mL×3) and concentrated to get initial product. The product thus obtained was purified by column chromatography, silica gel (60-120 mesh), using 80-100% EtOAc in petroleum ether as the eluent to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (d, J=7.6 Hz, 1H), 8.94 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 7.82 (t, J=8.8 Hz, 1H), 7.57-7.53 (m, 3H), 7.35 (d, J=8.8 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 4.16 (s, 3H). MS (ESI, positive ion) m/z: 485.1 (M+H).
Reaction SMILES: C1C2C(OC([NH:17][C:18]3([C:48]([OH:50])=[O:49])[CH2:23][CH2:22][C:21]([OH:47])([C:24]4[S:25][C:26]([C:29]5[CH:34]=[C:33]([NH:35][C:36]6[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=6)[CH:32]=[C:31]([CH3:46])[CH:30]=5)=[CH:27][N:28]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:17][C:18]1([C:48]([OH:50])=[O:49])[CH2:23][CH2:22][C:21]([OH:47])([C:24]2[S:25][C:26]([C:29]3[CH:34]=[C:33]([NH:35][C:36]4[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=4)[CH:32]=[C:31]([CH3:46])[CH:30]=3)=[CH:27][N:28]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(NC(=O)OC4c5ccccc5-c5ccccc54)(C(=O)O)CC3)s2)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(N)(C(=O)O)CC3)s2)c1
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
1-{[(9H-Fluoren-9-yloxy)carbonyl]amino}-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (0.079 g, 0.11 mmol) was dissolved in DMF (1.0 mL). Piperidine (0.086 g, 1.01 mmol) was added. After 15 minutes, the reaction mixture was directly purified by reverse phase HPLC to yield 1-amino-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (0.005 g, 0.01 mmol) as its TFA salt. MS ESI: [M+H]+ m/z 494.1. 1H NMR (600 MHz, CD3OD) δ 8.70 (d, J=4.9, 1H), 8.04 (s, 1H), 7.94-7.80 (m, 2H), 7.69 (d, J=7.6, 1H), 7.52-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.18-7.00 (m, 2H), 2.60-2.42 (m, 2H), 2.36 (s, 3H), 2.28-2.07 (m, 4H), 2.05-1.89 (m, 2H). rhSYK activity=+++. The starting material was prepared generally following the procedures described in Examples 32 and 33 using commercially available 1-{[{9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxocyclohexanecarboxylic acid.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[CH:38]1([N:30]2[C:31]3[C:26](=[C:25]([CH3:24])[C:34]([F:35])=[C:33]([N:9]4[CH2:10][CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8]4)[C:32]=3[F:37])[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:39][CH2:40]1
Reactant: c1cn(C2CCCNC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 66 h
Yield: 47.9 %

Procedure:
3-(1,2,3-triazol-1-yl)piperidine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-methyl-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed under stirring for 66 hrs and then concentrated. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 35 mg of desired product. m.p. 227°-228.5° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.53 (s, 1H), 8.65 (s, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 3.55-4.35 (m, 4H), 2.90 (s, 3H), 2.08-2.75 (m, 4H), 1.30-1.55 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].O.Cl[CH:14]([F:16])[F:15]>O1CCCC1>[F:15][CH:14]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 36.6 %

Procedure:
Under a dry argon atmosphere a mixture of 10.0 g (0.084 mole) of 4-cyanophenol, 33.6 g (0.84 mole) of sodium hydroxide, 110 ml of water, and 130 ml of tetrahydrofuran was stirred in a Morton flask and heated at reflux. During 1.25 hour, 8.6 g (0.99 mole) of chlorodifluoromethane was added to the reaction mixture. After complete addition, the mixture was allowed to cool to room temperature and was stirred for approximately 18 hours. The reaction mixture was poured into 500 g of ice water, the resulting mixture filtered, and the filtrate extracted with three 300 ml portions of diethyl ether. The ether extracts were combined, dried over anhydrous potassium carbonate, and filtered. The filtrate was evaporated under reduced pressure to give an oil which crystallized upon standing. The product was recrystallized from toluene/methylcyclohexane to give 5.2 g of 4-difluoromethoxybenzonitrile as a white solid, m.p. 36°-37° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.4 %

Procedure:
2-tert-Butoxycarbonylamino-thiazole-4-carboxylic acid (10.44 g, 42.74 mmol), N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.26 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9.83 g, 51.28 mmol), 1-hydroxybenzotriazole hydrate (6.93 g, 51.28 mmol), triethylamine (7.15 ml, 51.28 mmol) and 4-(dimethylamino)pyridine (1.04 g, 8.52 mmol) were combined in dichloromethane (200 mL) and stirred overnight at room temperature. The resulting solution was poured into ethyl acetate and washed with 0.2 M aqueous hydrochloric acid, water, brine and dried over magnesium sulfate. Solvent was removed and the crude was by purified over silica gel eluted with 80% v/v ethyl acetate in hexane to give [4-(methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester as a foam (17.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(O)cc2)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
2-Chloro-N-cyclopentyl-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equiv), 4-hydroxyphenylboronic acid (1 equiv), potassium carbonate (2.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.2 equiv), suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 100° C. for 16 h. The reaction mixture was loaded directly onto a silica gel column and purified using 5-100% ethyl acetate in hexane. Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 4-(2-chloro-4-(cyclopentylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (32.2% yield) as a yellow solid. MS (ESI) m/z 459.3 [M+1]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9](OC)=O)=[C:6]([OH:13])[C:5]=1[OH:14].CC1OC(C(OCC)=O)=C(O)C=1O.S(OC)(OC)(=O)=O.Cl>O>[CH3:3][CH:4]1[C:5](=[O:14])[C:6]([OH:13])=[C:7]([CH3:9])[O:8]1
Reactant: COC(=O)c1oc(C)c(O)c1O
Agent: CCOC(=O)c1oc(C)c(O)c1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC1=C(O)C(=O)C(C)O1
Temperature: 0 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A solution of 32 g of sodium hydroxide and 33 g of a mixture containing 37.1% of methyl 5-methyl-3,4-dihydroxy-2-furoate and 52.1% of ethyl 5-methyl-3,4-dihydroxy-2-furoate in 320 ml of water was allowed to stand at room temperature for 20 hours. To the resulting mixture is added at 0° C. in one hour 25.2 g of dimethyl sulphate followed by an additional stirring period of three hours at 0° C. The pH of the solution was adjusted to 6.5 by the addition of concentrated hydrochloric acid solution. Extraction with methyl t-butyl ether yielded 18.1 g of 2,5-dimethyl-4-hydroxy-3[2H] furanone of 88.8% purity (molar yield 76.6%).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]>CO.C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20]([S:2][CH3:1])[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: C[S-]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N(Cc1ccccc1)c1cc(SC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Sodium methanethiolate (180 mg) was added portion-wise to a stirred suspension of (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (300 mg) in methanol:THF (3:1, 4 ml). The mixture was sealed in a ReactiVial then left to stir at room temperature for 2 hours. The reaction mixture was diluted with methanol then pre-absorbed directly onto silica gel. The crude was columned on Isco Companion on a silica column (12 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 30:70 to 50:50 over 6 column volumes. The desired fractions were combined and evaporated to provide the title compound (297 mg) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O.CO>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[C:2]([F:1])[CH:3]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of EXAMPLE 92A (2.65 g, 8.2 mmol) in tetrahydrofuran (20 mL) was added lithium hydroxide monohydrate (688 mg, 16.4 mmol) in 20 mL of water and methanol added until a transparent solution formed. This mixture was stirred at ambient temperature for 2 hours and acidified with 2N hydrochloric acid to pH 2. The mixture was concentrated to about 10 mL, diluted with water and let stand at ambient temperature overnight. The white solid was collected by filtration, washed with water and dried to give the title compound (2.21 g). Recrystallization from methanol and water gave 1.61 g of title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:40](=[O:41])[NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: O=C=Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC(=O)Nc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(ff) In an analogous manner to that described in Example 24 (m), by reacting tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-pyridyl isocyanate there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(pyridin-2-ylcarbamoyloxy)-phenyl]-piperidine-1-carboxylate as a white solid; MS: 554 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][NH:6][NH2:7].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[C:17](=[O:16])[CH:18]=1
Reactant: NNCc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2C(F)(F)F)[nH]1
Reaction time: 8 h

Procedure:
46 g of 2-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 38.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallized from ethanol. The product was the compound identified above. Melting point: 184°, 22 g (34%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C@H:31]1[CH2:33][C@@H:32]1[C:34](Cl)=[O:35]>ClCCl>[OH:5][CH2:4][C@H:3]([NH:2][C:34]([C@H:32]1[CH2:33][C@@H:31]1[C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Reactant: CCCC(C)COc1ccc([C@@H](N)CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11](C1C=CC=CC=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+].[CH2:47](SCC(OCC)=O)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH2:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Reactant: CCOC(=O)CSCCc1ccccc1
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)CCc1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (20 g), a 2M ethanolic solution of sodium ethylate (42 cc) and ethyl (phenethylthio)acetate (15.7 g) in ethanol (200 cc). Diethyl 2-dimethylamino-5-phenethylthio-2,4-hexadienedioate (22.8 g) is thereby obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:21][CH2:22][CH3:23])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12]1)#[N:2].[ClH:24].CC([OH:28])C>CO>[ClH:24].[ClH:24].[O:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][CH:11]1[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:21][CH2:22][CH3:23])=[N:3][C:1]([NH2:2])=[O:28]
Reactant: CCNC(=NC#N)NCCCNCC1CCc2ccccc2O1
Reactant: CC(C)O
Agent: Cl
Solvent: CO
Product: CCNC(=NC(N)=O)NCCCNCC1CCc2ccccc2O1

Procedure:
A mixture of 3.1 g (±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propyl]-N'-ethylguanidine in a solution of 10 ml hydrochloric acid in 2-propanol and 50 ml methanol was stirred and refluxed for 30 minutes. The solvent was evaporated. The residue was dissolved in water and this mixture was alkalized with aqueous NaOH (10%). This mixture was extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 / CH3OH/(NH3)90:10). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and into the hydrochloric acid salt (1:2) with 2-propanol saturated with HCl. The salt was filtered off and recrystallized from 2-propanol. The crystals were filtered off and dried, yielding 2.95g (±)-N-[[[3-[[(3 ,4-dihydro-2H-1-benzopyran-2-yl) methyl]amino]propyl]amino](ethylamino)methylene]urea dihydrochloride; mp. 182.2° C. (interm. 51).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[N:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O.CN(C=O)C>[CH3:11][N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([C:50]3[N:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=3)[CH:19]=[CH:18][C:5]=2[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:8]1
Reactant: Cc1ccc(Cl)nn1
Reactant: CN1CCN(c2ccccc2)c2ccc(Br)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)CN(C)CCN3c2ccccc2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A round bottomed flask was charged with 7-bromo-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.22 g, 0.7 mmol) from step A above, bis(pinacolato)diboron (0.20 g, 0.77 mmol), potassium acetate (0.21 g, 2.1 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (57 mg, 0.07 mmol) and DMF (3.5 mL). The mixture was degassed with nitrogen (3×) and then stirred at 60° C. overnight. The mixture was cooled to room temperature, and cesium carbonate (0.68 g, 2.1 mmol), 3-chloro-6-methylpyridazine (0.14 g, 1.1 mmol) and water (1.8 mL) were added to it. The mixture was degassed with nitrogen (3×) and then stirred at 60° C. for 3 hours. After cooling, the mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride (3×20 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride, then 10:1 methylene chloride/methanol) to yield the desired 4-methyl-7-(6-methylpyridazin-3-yl)-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.16 g, 67%) as a grey solid.