Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1Br)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[C:21]1[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)cc(OC)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(C(=O)OC)cc(OC)c1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 3-ethoxy-4-bromo-5-methoxybenzoate (300 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg) were dissolved in DME in a nitrogen atmosphere, and potassium phosphate (661 mg) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride-CH2Cl2 complex (85 mg) were added to it at room temperature and degassed. The reaction liquid was stirred overnight at 90° C., then cooled to room temperature, water was added to it, and filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 40/60) to obtain the title compound as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:14][CH2:15]O>>[Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: CC(C)(CBr)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)CBr

Procedure:
3-Bromo-2,2-dimethylpropanoic acid (200 mg) was dissolved in EtOH (5 ml) and treated with concentrated H2SO4 (0.4 ml). This mixture was heated at reflux overnight then evaporated. The residue was extracted from H2O with EtOAc (×2) and the combined organic solutions dried and evaporated to give the title compound (316 mg) as a clear oil. δH (CDCl3, 400 MHz) 1.20 (3H, t), 1.32 (6H, s), 3.51 (2H, s), 4.18 (2H, q).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:34]1(=[O:44])[N:38]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12
Reactant: OC#CCCCCc1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of 6-(3-chlorophenyl)hexyn-1-ol (11.5 g, 55 mmol), triphenylphosphine (14.5 g, 55 mol) and phthalimide (8.1 g, 55 mol) in dry THF (110 ml) was treated with a solution of diethylazodicarboxylate (9.6 g, 55 mmol) in THF (20 mol) over several minutes. After 16 h, violates were removed in vacuo and the residue treated with ether. The precipitated solid was removed, the filtrate evaporated and the residue purified by flash chromatography on silica using dichloromethane as eluant. Evaporation of the appropriate fractions gave the product as a solid (16.5 g, 89%)
Reaction SMILES: [CH2:1]1[CH2:9][N:8]2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])[CH2:7]2)[C@H:3]([OH:12])C1.C1(=O)O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](O)[C@@H]1[OH:15]>>[OH:12][C@H:3]1[CH:4]2[N:8]([CH2:7][C@@H:6]([OH:10])[C@H:5]2[OH:11])[CH2:9][C@H:1]1[OH:15]
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](O)[C@@H]1O
Product: O[C@@H]1CN2C[C@@H](O)[C@@H](O)C2[C@@H]1O

Procedure:
The tetrahydroxypyrrolizidone (1) is an analogue of 1,8-diepiswainsonine. A similar analogue of swainsonine can be made by analogous methods starting with D-glycero-D-talo-heptono-1,4-lactone to produce the novel (1S, 2R, 6R, 7S)-1,2,6,7-tetrahydroxypyrrolizidine.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[N:18][C:17]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[S:20][C:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=2)=[C:17]([CH3:28])[N:18]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccccc3Cl)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2sc(-c3ccccc3Cl)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-(4-{2-[2-(2-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-(4-{2-[2-(2-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:39]([NH:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH3:41]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[N:42]([CH2:43][CH2:44][CH3:45])[CH2:39][CH2:40][CH3:41])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CCCNCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (2.0 g, 7.72 mmol) and HATU (3.52 g, 9.27 mmol) in DMF (70 mL) was stirred at room temperature for 10 min. Then dipropylamine (0.78 g, 1.1 mL, 7.72 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (2.6 g, 99.5% yield): 1H NMR (CD3OD, 500 MHz) δ ppm 0.78 (3H, t, J=5 Hz), 1.01 (3H, t, J=5 Hz), 1.60 (2H, m), 1.74 (2H, m), 3.21 (2H, m), 3.49 (2H, m), 3.96 (3H, s), 7.79 (1H, m), 7.94 (1H, m), 8.23 (1H, m). HPLC retention time: 2.018 min (method B). MS (ESI) (M+H)+ 342.09.
Reaction SMILES: [S:1]([NH:5][C:6](=[NH:11])[CH2:7][CH2:8][S:9][CH3:10])(=[O:4])(=[O:3])[NH2:2].[H-].[Na+].C1(O[C:21]#[N:22])C=CC=CC=1>O1CCCC1.C(OCC)C>[NH2:22][C:21]1[NH:2][S:1](=[O:3])(=[O:4])[N:5]=[C:6]([CH2:7][CH2:8][S:9][CH3:10])[N:11]=1
Reactant: CSCCC(=N)NS(N)(=O)=O
Reactant: N#COc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSCCC1=NS(=O)(=O)NC(N)=N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of N-sulfamyl-3-(methylthio)propionamidine (4.9 gm, 25 mmol) in dry tetrahydrofuran (75 ml) under nitrogen there was added 60% sodium hydride in mineral oil (1.0 gm, 25 mmol). This mixture was warmed at 60° C. for 1/2 hour as a copious precipitate formed. To this suspension, a solution of phenylcyanate (3.0 gm, 25 mmol) in dry THF was added dropwise giving a homogeneous solution. After 1/2 hour, additional 60% sodium hydride in mineral oil (1.0 gm, 25 mmol) was added and the resultant solution warmed at 50° C. for 20 hours. The reaction mixture was diluted with diethyl ether and the precipitate collected by filtration. This precipitate was dissolved in water, acidified with dilute HCl, filtered and the aqueous solution extracted with 3% methanol/chloroform and then the water removed under vacuum. The residue was extracted with acetonitrile, filtered, and the extract evaporated to give crude product (2.0 gm). This material was chromatographed on silica gel and eluted with 5- 10% methanol/chloroform. Upon concentration of the appropriate fractions, the product crystallized, (1.4 gm), m.p. 243°-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)c(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-nitroaniline (4.33 g), benzenesulphonyl chloride (3.25 ml) and pyridine (2.5 ml) was stirred and heated to 100° C. for 18 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and 2M aqueous hydrochloric acid. The organic phase was washed with water, dried and evaporated. The residue was recrystallised from ethyl acetate to give N-(2-chloro-4-nitrophenyl)benzenesulphonamide (6.07 g), m.p. 155°-157° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[H-].[Na+].O>CN(C)C=O>[Cl:10][C:8]1[C:7]([F:11])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[N:9]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)nc1OCC(F)(F)F
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (900 mg, 5.7 mmol), 2,2,2-trifluoro-ethanol (570 mg, 5.7 mmol), and NaH (60%) (273 mg, 6.8 mmol) in N,N-dimethylformamide (15 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed to give the title compound (1100 mg, 76%). MS (DCI/NH3) m/z 255 (M)+, 257 (M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2CC2(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
216 mg (465 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoate (mixture of two racemic diastereomers) in 1 ml of dichloromethane and 537 μl (6.97 mmol) of TFA were reacted according to General Method 6A. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 88 mg (44% of theory)
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])(=[O:35])[NH2:36]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 502.3 [(M+H)+]; mp 249-250° C.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Ca+2:26].[OH-]>C(O)(=O)C>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ca+2:26].[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.25 h

Procedure:
108.8 g of behenic acid and 24.8 g of calcium hydroxide were stirred at 60° to 70° C., followed by the addition of 0.4% of acetic acid. The total stirring time was 15 minutes. During the reaction, the temperature rose to 90° C. A whitish, fine, loose powder having a Ca content of 10.1%, a melting temperature of 140 to more than 250° C., and an acid value of 4.3 was obtained.
Reaction SMILES: [Cl:1][C:2](=[CH2:15])[CH2:3][C:4]1[C:5]([OH:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:17](=C)COC1C=CC=CC=1C(OC)=O>>[Cl:1][C:2](=[CH2:15])[CH2:3][C:4]1[C:5]([OH:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:17])=[O:8]
Reactant: C=C(Cl)Cc1cccc(C(=O)OC)c1O
Reactant: C=C(Cl)COc1ccccc1C(=O)OC
Product: C=C(Cl)Cc1cccc(C(=O)OCC)c1O
Temperature: 260 °C
Yield: 88 %

Procedure:
Methyl 3-(2-chloro-2-propenyl)-2-hydroxybenzoate. 274.1 g (1.21 mole) of methyl 2-(2-chloro-2-propenyloxy)-benzoate, placed in a 2 liter round-bottomed flask, are carefully degassed with argon. This is then heated as rapidly as possible to 260° C. At this temperature, an exothermic reaction takes place suddenly: the temperature increases to 293° C. by itself and reflux and blackening of the reaction mixture takes place. After cooling to ambient temperature, the product is distilled under reduced pressure. 241.1 g of ethyl 3-(2-chloro-2-propenyl)-2-hydroxybenzoate are obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][C:30](OC)=[O:31].CN(C)C=O>O>[O:31]=[C:30]1[CH2:29][S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26]1
Reactant: COC(=O)CBr
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NC(=O)CS1)OCO3
Temperature: 85 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 1.00 g (2.6 mmol) of the starting material I, 1.19 g (7.78 mmol) of methyl bromoacetate and 10 ml of dimethylformamide was stirred at 80-90° C. for 1 h. After diluting with water the obtained crude product was purified by refluxing in methanol to yield 1.00 g (91%) of the title compound; Mp.: 218-220° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>C1COCC1.CN(C=O)C>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:9]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1-n1cncn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
To a solution of 2,4-difluorobenzonitrile (10 g, 72 mmol), dissolved in THF (20 mL) and DMF (40 mL), was added 1,2,4-triazole sodium salt (6.3 g, 70 mmol) and the resulting mixture stirred at 90° C. for 3 h, after which it was filtered and concentrated. The remaining residue was adsorbed onto silica gel and purified by flash column chromatography eluting with 0%–30% ethyl acetate/hexanes to give the title compound as colorless needles (2.46 g, 18% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 8.89 (1H, s), 8.19 (1H, s), 7.85 (1H, dd, J=8.7, 5.6 Hz), 7.60 (1H, dd, J=8.8, 2.4 Hz), 7.28–7.24 (1H, m). LCMS (M+H) calcd for C9H6N4F: 189.05; found: 189.13.
Reaction SMILES: [CH2:1]([N:3]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:13]3[CH:18]=[CH:17][C:16](O)=[CH:15][C:14]3=[O:20])=[CH:9]2)=[N:4]1)[CH3:2].P(Br)(Br)([Br:23])=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:23][C:16]1[CH:17]=[CH:18][N:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:11]([CH3:12])[N:3]([CH2:1][CH3:2])[N:4]=3)[CH:9]=2)[C:14](=[O:20])[CH:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCn1nc2ccc(-n3ccc(O)cc3=O)cc2c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc2ccc(-n3ccc(Br)cc3=O)cc2c1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 1-(2-ethyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (1.07 g) in N,N-dimethylformamide (20 ml) was added phosphorus oxybromide (1.37 g) at room temperature, and the mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-hexane to give the title compound (680 mg).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:23]([OH:25])[CH3:24]>O>[CH2:23]([O:25][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[CH3:24]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (600 mg, 2.26 mmol) in ethanol (20 mL) was added sodium hydroxide (400 mg, 10.0 mmol) in water (2 mL) and heated at 80° C. for 24 h. The reaction mixture was neutralized with aqueous hydrochloric acid (1 N), the solvent was evaporated under reduced pressure and used to the next step directly. MS m/z 292.3 (M+1), retention time=0.99 min.
Reaction SMILES: [CH:1]12[NH:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19]([N:7]1[CH:6]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:20]
Reactant: C1CCC2NC2C1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A mixture of 1.45 g of 7-azabicyclo[4.1.0]heptane, 2 ml of triethylamine and 3 ml of ethyl acetate was added dropwise to a mixture of 10 ml of ethyl acetate and 2.3 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid chloride under ice-cooling. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.8 g of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:31])([F:30])[S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:26]\[C:25]3[CH:28]=[CH:29][C:22]([S:21][C:20]([F:31])([F:19])[F:30])=[CH:23][CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (1.2 g, 4.858 mmol) in toluene 40 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (1 g, 4.858 mmol). PTSA (1.84 g, 9.716 mmol) was added and the reaction mixture was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 73, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 73 was eluted at 37% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.CN.CO.CC(O)=O.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cnc2ccccc2c1
Yield: 48.2 %

Procedure:
A solution of 3-quinolinecarboxaldehyde (1.5 g,10 mmole), 2.0 M CH3NH2/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), and NaBH3CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the title compound (0.83 g, 24%) as a slightly yellow viscous oil: MS (ES) m/e 173 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]([C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH3:6])([O-])=O.Cl.[N:21]#[C:22][NH2:23]>[Pd]>[CH2:5]([C:4]1[NH:1][C:22]([NH2:23])=[N:21][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:6]
Reactant: CCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Reactant: N#CN
Agent: [Pd]
Agent: Cl
Product: CCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
3-Nitro-9-phenylnonan-4-one (0.050 g, 0.19 mmol) reacted with concentrated HCl (0.95 mmol) and palladium, 5 wt. % on activated carbon (0.081 g, 0.038 mmol) under H2, then reacted with cyanamide (0.040 g, 0.95 mmol) according to the general procedure. Purification by column chromatography gave 0.014 g (29%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.25 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (m, 4H), 1.63 (m, 4H), 1.28 (m, 2H), 1.13 (t, J=7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 142.4, 128.2, 128.1, 125.5, 123.6, 121.3, 35.5, 31.1, 28.7, 28.1, 22.9, 16.5, 13.1 ppm; IR νmax (cm−1) 3327, 2934, 1680, 1453, 1016, 749; HRMS (FAB) calcd for C16H23N3 (MH+) 258.1965, found 258.1973.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[CH:12](I)([CH3:14])[CH3:13].Cl>C(O)C>[NH2:3][C@@H:4]([C:5]([S:8][CH:12]([CH3:14])[CH3:13])([CH3:7])[CH3:6])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)SC(C)(C)[C@H](N)C(=O)O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
NaH (1.3 g) was added in portions to 70 mL ethanol while cooling. Subsequently D-penicillamine (4.0 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which isopropyl iodide (2.8 mL) was added, The mixture was allowed to stir 16 h at ambient temperature. 2 N HCl was added followed by evaporation of the volatiles to give 11.9 g crude 2-(R)-amino-3-isopropylsulfanyl-3-methyl-butyric acid, which was used in the next step without further purification.