Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:21]([NH2:25])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(N)ccc21
Reaction time: 20 h
Yield: 115.6 %

Procedure:
A suspension of sodium dithionite (978 mg, 4.21 mmol) and 4-(2-fluoro-4-iodo-phenylamino)-5-nitro-indazole-1-carboxylic acid tert-butyl ester (700 mg, 1.4 mmol) in water (35 mL) was treated with a 1:1 mixture of THF:dioxane (34 mL), the homogeneous reaction mixture stirred at room temperature for 4 hours. Further sodium dithionite (978 mg, 4.21 mmol) was added and stirring continued for 20 hours. The reaction mixture was basified by the addition of saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate (150 mL). The organic extract was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (758 mg, quant.). LCMS (Method B) RT=4.09 min, [M+H]+=469.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(CCN(C)C)C.[Li]CCCC.[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](N(OC)C)=[O:47])[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](=[O:47])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cscn1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)c1nccs1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of thiazole (0.035 mL, 0.5 mmol) and TMEDA (0.068 mL, 0.45 mmol) in anhydrous THF (1.0 mL) cooled to −60° C. is added n-BuLi (0.17 mL, 0.43 mmol). After stirring for 20 min at −60° C., a solution of N,β,β-trimethyl-L-phenylalanyl-N1-{(1S,2E)-1-isopropyl-4-[methoxy(methyl)-amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (52 mg, 0.1 mmol, from Example 52, in anhydrous THF (0.5 mL) is added. The purple reaction mixture is stirred for 2 h from −60° C. to room temperature, quenched with saturated aqueous ammonium chloride (1.5 mL). The reaction mixture is extracted with ethyl acetate three times. The combined organic layers are dried (Na2SO4), filtered and concentrated. The residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile) to give 56 mg (86%) of desired product as a yellow solid. HRMS (ESI) calcd for C30H44N4O3S [M+H] 541.3207, found 541.3203.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][CH2:47][C:48]1[C:49](=[O:56])[NH:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54].O>ClCCl>[CH3:54][C:53]1[CH:52]=[C:51]([CH3:55])[NH:50][C:49](=[O:56])[C:48]=1[CH2:47][NH:46][C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:2]=1[CH3:1])=[O:20]
Reactant: Cc1c(C(=O)O)c2ccncc2n1C(C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3cnccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.3 %

Procedure:
A mixture of 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (280 mg, 1.0 mmol) was added HATU (456 mg, 1.2 mmol), TEA (1 g, 10 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (182 mg, 1.2 mmol) in anhydrous dichloromethane (30 mL) was stirred at room temperature for 16 hours. To the reaction mixture was added water (10 mL), extracted with dichloromethane (30 mL: 2). The organic layers were combined and concentrated to give a residue. The residue was recrystallized from MeCN to afford compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide as an off-white solid (80 mg, 21.6%). LRMS (M+H+) m/z: calcd 414.21. found 414. 1H NMR (400 MHz, Methanol-d4) δ: 8.84 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.44-7.37 (m, 5H), 6.09 (s, 1H), 6.01-5.99 (m, 1H), 4.49 (s, 2H), 2.73 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H), 2.06 (d, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].ClC1C=CC(N(C(=O)CC)C2C3C(=CC=C(C=CC(O)=O)C=3)N(C(=O)C3C=CC(F)=CC=3)C(C)C2)=CC=1.C(N(C1C=CC(Cl)=CC=1)[C@H]1C2C(=CC=CC=2)N(C(C2C=CC(CCC(O)=O)=CC=2)=O)[C@@H](C)C1)(=O)C>>[C:9]([N:8]([C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:14]([CH3:32])[CH2:13]1)[C:5]1[CH:6]=[CH:7][C:2]([CH2:35][CH2:34][C:33]([OH:37])=[O:36])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: C=CC(=O)O
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Br)cc3)C[C@@H]2C)cc1
Agent: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Agent: CCC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(CCC(=O)O)cc3)C[C@@H]2C)cc1

Procedure:
(2S,4R)-3-(4-{Acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-propionic acid was prepared from (2S,4R)-N-(4-bromo-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide. (2S,4R)-N-(4-Bromo-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was converted to the acrylic acid using the same procedure described in the synthesis of (±)-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid. The reduction and saponification were carried out as in the procedure describing the preparation of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-propionic acid.
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7][N:8]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([NH:23][NH2:24])=O>ClC1C=CC=CC=1Cl>[NH2:17][C:18]1[CH:19]=[C:20]([C:21]2[N:8]3[CH2:7][CH2:6][CH:5]([C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[CH2:4][C:3]3=[N:24][N:23]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: COC1=NCCC(c2ccc(C#N)cc2)C1
Reactant: Cc1ccc(C(=O)NN)cc1N
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nnc3n2CCC(c2ccc(C#N)cc2)C3)cc1N
Temperature: 150 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of 4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound 347.3, 5.00 g, 23.36 mmol, 1.00 equiv) in 1,2-dichlorobenzene (100 mL) was added 3-amino-4-methylbenzohydrazide (compound 347.4, 4.63 g, 28.0 mmol, 1.20 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. After cooling to ambient temperature, the resulting mixture was purified using silica gel column chromatography with dichloromethane/methanol (1:0˜100:1) as eluent to furnish 2.40 g (31%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[F:10])[O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccc(Br)cc1O
Product: Fc1ccccc1-c1nc2ccc(Br)cc2o1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 2-fluorobenzoic acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH2:20])=O)=[CH:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]#[N:20])=[CH:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: NC(=O)c1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2[nH]1
Solvent: ClC(Cl)Cl
Product: N#Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2[nH]1

Procedure:
A solution of 8.50 g. (0.026 mol) of 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]indole-2-carboxamide in 100 ml. of chloroform and 100 ml. of an ether-chloroform solution of polyphosphate ester was heated under reflux for 45 minutes and concentrated under vacuum. The residue was mixed with ether and water and made basic with sodium bicarbonate. The ether layer was then dried and concentrated, and the residue was mixed with dichloromethane. Filtration removed a little starting material and concentration gave several crops of crude 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]indole-2-carbonitrile. The mother liquors were absorbed on silica gel from benzene solution. Elution with 0-10% ether in dichloromethane gave further 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]indole-2-carbonitrile. Recrystallization of the combined material from dichloromethane gave 5.60 g. (70%) of 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]indole-2-carbonitrile as colorless crystals, m.p. 183°-185°. The analytical sample had m.p. 181°-184°.
Reaction SMILES: COC1C=CC(C[N:8]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:22])[CH2:19][CH2:18][O:17][C:16]=3[CH:33]=2)(=[O:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:35]1[CH:36]=[CH:37][N:38]=[C:34]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:22])[CH2:19][CH2:18][O:17][C:16]=2[CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To a solution of 4-nitrophenyl 7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (0.050 g, 0.086 mmol) in DCM (0.172 ml) was added trifluoroacetic acid (0.165 ml, 2.146 mmol). The reaction was stirred at RT for 15 minutes until complete deprotection. The reaction was concentrated in vacuo and purified via 500-mg SCX column (product eluted cleanly with methanol wash) to yield, after concentration, 4-nitrophenyl 7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3 H)-carboxylate (0.036 g, 0.078 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1 H) 8.28-8.38 (m, 2 H) 8.06 (d, J=8.71 Hz, 1 H) 7.55-7.64 (m, 2 H) 7.34 (dd, J=8.75, 2.20 Hz, 1 H) 7.22-7.30 (m, 2 H) 6.83 (d, J=4.60 Hz, 1 H) 4.36-4.48 (m, 2 H) 4.02-4.11 (m, 2 H). m/z (ESI) 462.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]1)=[CH:8][C:7]([C:25]([F:28])([F:27])[F:26])=[CH:6][CH:5]=2.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>>[CH3:1][C@H:2]1[C@@H:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([F:28])([F:26])[F:27])[CH:8]=2)[NH:3]1
Reactant: Cc1[nH]c2ccc(C(F)(F)F)cc2c1CCN1CCN(c2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Nc2ccc(C(F)(F)F)cc2[C@@H]1CCN1CCN(c2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 1.2 g. of the product of Example 12 and 30 ml. of trifluoroacetic acid, heated to 50° C. is added 3.0 ml. of triethylsilane. This solution is stirred and heated at 50° C. for 96 hours. The reaction mixture is poured onto chopped ice and 50 ml. of 10 N sodium hydroxide. Then the aqueous mixture is extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to yield cis-2-methyl-5-trifluoromethyl-3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline as the product. This compound is dissolved in ethyl acetate and acidified with anhydrous hydrogen chloride. The solid which precipitates is collected by filtration to provide the desired cis indoline dihydrochloride as the product of the Example.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][Cl:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Product: O=C(CCl)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (15.0 g, 69.1 mmol) was added drop wise 2-chloroacetyl chloride (9.4 g, 82.9 mmol) under nitrogen. After refluxing for 1.5 h, the reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. Crystallization from ethyl acetate/hexane afforded N-(4-bromo-2-nitrophenyl)-2-chloroacetamide (19.4 g, 66.1 mmol, 96%) as yellow needles.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[O:7])=[CH:4][N:3]=1.[NH2:16][NH2:17].C1(C)C=CC=CC=1>C(O)(C)C>[NH:16]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[O:7])=[CH:4][N:3]=1)[NH2:17]
Reactant: NN
Reactant: COCCCNC(=O)c1ccc(Cl)nc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COCCCNC(=O)c1ccc(NN)nc1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(3-methoxypropyl)nicotinamide (6.6 g, 28.9 mmol) and hydrazine (4.53 mL, 144 mmol) in isopropanol (100 mL) was heated at 80° C. for 21 h. More hydrazine (3 mL) was added and heating continued at 80° C. for 24 h. The reaction was then concentrated in vacuo to give a tan oil which was reconcentrated from toluene to give the title compound as its hydrochloride salt as a white solid in quantitative yield. MS m/z 225 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.78 (m, 2H) 3.18-3.30 (m, 5H) 3.35 (t, J=6.3 Hz, 2H) 6.68 (d, J=8.8 Hz, 1H) 7.87 (dd, J=8.8, 2.3 Hz, 1H) 7.99 (br. s., 1H) 8.20 (t, J=5.6 Hz, 1H) 8.49 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:18])([F:17])[C:13]([CH3:16])([OH:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][C:13]([CH3:16])([CH3:14])[C:12]([F:18])([F:17])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (2.82 g) and 1,1,1-trifluoro-2-methyl-propan-2-ol (2.3 ml) in DMF (90 ml) under an argon atmosphere was added under ice cooling NaH (0.914 g, 55% suspension in oil) and the mixture was stirred for 3 h at RT. It was then partitioned between diethyl ether and water, the layers were separated, dried over Na2SO4 and the solvent was evaporated off to give 1-nitro-4-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzene as a brown oil (4.9 g) that was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[Br:14].O.[NH2:17][NH2:18]>CCO>[Br:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]([O:2][NH:17][NH2:18])=[O:15]
Reactant: NN
Reactant: COC(=O)c1cc(OC)c(OC)cc1Br
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(C(=O)ONN)cc1OC
Temperature: -20 °C
Yield: 82.1 %

Procedure:
A mixture of 0.960 g (3.48 mmol) of 7, 1.60 g (35 mmol) of hydrazine hydrate (62% hydrazine), and 5 mL of EtOH was refluxed for 15 h. The mixture was cooled to −20° C., vacuum filtered, washed with 50 mL of ice-cold 1:1 EtOH:H2O, and dried to give 0.832 g (87% yield) of (2-bromo-4,5-dimethoxy benzoyloxy) hydrazine (8) as a white, needle-like crystalline solid. The above procedure was repeated on 2.79 g of the starting ester 7 to result in 2.77 g (99% yield) of 8. 1H NMR (200 MHz, CDCl3) δ 6.97 (s, 1H), 6.86 (s, 1H), 3.85 (s, 6H). HRMS Calculated for C9H12O3N2Br 275.0031. found 275.0037.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O.C(O)C>[CH:25]1[CH:24]=[C:21]2[C:22]([N:2]([CH2:3][C:4]([NH2:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a stirred solution of glycinamide hydrochloride (2.20 g, 20.0 mmoL) and sodium carbonate (2.54 g, 24 mmoL) in 25 mL of water is added N-carbethoxyphthalimide (4.38 g, 20.0 mmoL). The resulting suspension is stirred for 1.5 hour and then filtered to afford 3.22 g (79%) of the crude product as a white powder. The crude product is slurried in 200 mL of refluxing ethanol. The resulting suspension after cooling to room temperature is filtered and the solid dried in vacuo (60° C., <1 mm) to afford 2.65 g (65%) of N-phthaloylglycinamide as a white powder: mp 199-201° C.; 1H NMR (DMSO-d6) δ8.00-7.8 (m, 4H, Ar), 7.70 (br s, 1H, CONH2), 7.26 (br s, 1H, CONH2), 4.16 (s, 2H, CH2); 13C NMR (DMSO-d6) δ167.8, 167.5, 134.4, 131.7, 123.1, 39.9. Anal. Calcd for C11H10N2O3. Theoretical: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.49; H, 4.59; N, 12.82.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccc2)cnn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)cnn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 240 mg (0.71 mmol) 5-benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-ethyl]-2H-pyridazin-3-one (example 21.1a) in 2.0 mL of DCM is added at 0° C. 134 μL (1.43 mmol) phosphorus tribromide. The mixture is stirred 4 h at RT, cooled to 0° C. and aqueous saturated NaHCO3-solution is added until pH >7. The layers are separated, the aqueous phase is extracted with DCM and the combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3C=CC(CO)=NC=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28].CC[N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])C.CS([Cl:44])(=O)=O.O>C(Cl)Cl>[Cl:44][CH2:39][C:37]1[CH:38]=[C:13]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])=[C:2]([CH3:1])[CH:7]=3)[O:12][N:11]=2)[CH:36]=[CH:34][N:33]=1
Reactant: Cc1cc(-c2nc(-c3ccc(CO)nc3)no2)ccc1-c1ccccc1C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2nc(-c3ccnc(CCl)c3)no2)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of (5-(5-(2-methyl-2′-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanol (0.103 g; 0.28 mmol) and DIEA (0.087 mL; 0.50 mmol) in DCM (2.5 mL) was added methanesulfonyl chloride (0.021 mL; 0.27 mmol). The mixture was stirred at ambient temperature for 1 hour and water added. The mixture was passed through a hydrophobic frit and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title product (0.085 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 8.78 (1 H, d, J=5.1 Hz), 8.25 (1 H, s), 8.15 (1 H, s), 8.08 (1 H, dd, J=8.0, 1.7 Hz), 8.01 (1 H, dd, J=5.0, 1.5 Hz), 7.81 (1 H, d, J=8.0 Hz), 7.63 (1 H, t, J=7.6 Hz), 7.54 (1 H, t, J=7.8 Hz), 7.36 (1 H, d, J=7.9 Hz), 7.29-7.23 (1 H, m), 4.79 (2 H, s), 2.16 (3 H, s).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:12][CH2:13][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3]>Cl>[ClH:1].[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C:7]=2[CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)C1CCc2cc(C(=N)N)sc2C1
Agent: Cl
Product: N=C(N)c1cc2c(s1)CC(C(=O)O)CC2
Temperature: 70 °C
Reaction time: 9 h
Yield: 92.5 %

Procedure:
A mixture of 2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.15 g), and 6 N HCl (10 ml) was stirred at 70° C. for 9 hours. The resulting precipitate was washed with Et2O to give 2-amidino-6-carboxy-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (0.96 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][S:15][CH2:14][CH2:13]1.[ClH:28]>O1CCOCC1>[ClH:28].[NH2:20][CH:17]1[CH2:16][S:15][CH2:14][CH2:13][N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc3ccccc3c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CSCCN(Cc2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
510 mg of 42 (1.32 mmol) are taken up in a 25 ml round-bottomed flask and 10 ml of a solution of hydrogen chloride in dioxane (4M) are added. The mixture is stirred for 3 hours at room temperature under argon. After evaporating off the solvent, 510 mg of amine 43 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18](O)([C:20]([O:22]C)=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.CC[C@]12C=C(C(OC)=O)N3C4=C(CCN([C@@H]14)CCC2)C1C=CC=CC=13>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[N:17]3[C:9]4=[C:10]([C:11]5[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2
Reactant: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CC[C@@]12C=C(C(=O)O)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Yield: 60 %

Procedure:
According to the Hungarian Patent Specification No. 163,143 racemic, cis compounds of the formula (I) and optically active, cis compound of the formula (Ic) were prepared by hydrolyzing the pharmaceutically active vincamine and converting the vincaminic acid obtained into a desired ester from which the corresponding apovincaminic acid ester was obtained by splitting off water; or alternatively, vincamine was first converted into apovincamine by splitting off water which was then subjected to hydrolysis and the apovincaminic acid obtained was converted into a desired ester. This process is disadvantageous in that at first vincamine should be prepared by a multi-step synthesis from which the corresponding apovincaminic acid esters can be prepared with a yield of at most 60% only.