Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[C:9]([O:13][C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:9]([O:13][C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B, reaction of 1-methyl-1H-imidazole-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and NaBH(OAc)3 gave {4-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white foam.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: CC/C=C/C(=O)OC
Product: CCC(CC(=O)OC)N1CCCCC1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of 500 g of methyl 2-trans-pentenoate and 372 g of piperidine was heated at 100° C. for 24 hours. 562 g (64% of theory) of methyl 3-piperidinovalerate of boiling point 75°-77° C./2 mbar were obtained by fractional distillation.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH2:33][CH2:32][N:17]3[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][O:29][CH2:28][CH2:27][NH:26]4)[C:20](=[O:23])[C:21]([OH:22])=[C:16]3[C:15]2=[O:34])=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:67][N:68]([C:70](=[O:74])[C:71](O)=[O:72])[CH3:69]>CN(C=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:33][CH2:32][N:17]3[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][O:29][CH2:28][CH2:27][N:26]4[C:71](=[O:72])[C:70]([N:68]([CH3:69])[CH3:67])=[O:74])[C:20](=[O:23])[C:21]([OH:22])=[C:16]3[C:15]2=[O:34])=[CH:35][CH:36]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: O=C1c2c(O)c(=O)n(CC3COCCN3)c(=O)n2CCN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)C(=O)C(=O)N1CCOCC1Cn1c(=O)c(O)c2n(c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Fluorobenzyl)-9-hydroxy-7-(morpholin-3-ylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione mono TFA salt (50 mg, 0.096 mmol, from Example 17) in DMF (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.145 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.145 mmol), triethylamine (30 μL, 0.212 mmol), and (dimethylamino)(oxo)acetic acid (22 mg, 0.12 mmol). The reaction was stirred overnight at room temperature and equal amount of the reagents were added to the flask in the morning. After two hours the reaction was purified by prep HPLC on a C18 stationary phase with a water/acetonitrile/TFA gradient. The title compound as obtained as a white solid after lyophilization from dioxane. 1H NMR (400 MHz, d6 DMSO) Mixture of rotamers, approximately 1:1. δ 11.8 (2bs, 1H), 7.40 (m, 2H), 7.21 (m, 2H), 4.61-4.77 (m, 4H), 4.05 (m, 0.5H), 3.78-3.99 (m, 5H), 3.67 (m, 0.5H), 3.55-3.61 (m, 3H), 3.31-3.43 (m, 1.5H), 3.08 (m, 0.5H), 2.84, 2.81 (2s, 3H), and 2.76, 2.75 (2s, 3H). HRMS (FT-ICR) C23H26FN5O7+H=504.1873; calculated 504.1889.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[H-].[Na+].I[CH3:14]>C1COCC1.CN(C=O)C.[NH4+].[Cl-]>[CH3:14][O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: OCCc1ccccc1Br
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCc1ccccc1Br
Reaction time: 0.5 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in THF/DMF (4/1; 0.12M) at 0° C. was added NaH (60% dispersion in oil; 1.5 eq). The mixture was stirred for 30 min then iodomethane (2 eq.) was added. The final mixture was stirred for 12 h at room temperature, poured in saturated aqueous NH4Cl and then extracted with Et2O. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi Flash from ISCO), eluting with Hex/EtOAc 0 to 50%, afforded the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:8]=[CH:7][C:6]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:41][C:2]([F:1])([F:40])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:7][C:6]=1[CH2:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:27][CH2:28]1)=[O:22]
Reactant: CC(C)(C)OC(=O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(tert-butyloxycarbonylmethoxy)-phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.72 mg, 1.2 mmol) from Step 1 above in CH2Cl2 (20 mL) was added TFA (20 mL). After standing at ambient temperature for 1.5 h the solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a H2O:CH3CN gradient containing 0.1% TFA. The product-containing fractions were combined and lyophilized to give the title compound as an amorphous powder.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].F[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]>C1COCC1.CC(O)C>[CH:1]([O:4][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)O
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of isopropanol (225 mL) and small chunks of sodium metal (1.92 g, 83.6 mmol) were heated to reflux for 2.5 hours, until the sodium was consumed. The resulting solution was added while still hot to a solution of 4-fluoro-3-nitro-benzenesulfonamide (8.37 g, 38.0 mmol, example 2, step b) in THF/iPrOH (1/1, v/v, 150 mL) over a 10 minute period and stirred at room temperature for 3.5 hours. The reaction mixture was partitioned between EtOAc and brine and 1 N aqueous HCl. The organic phase was then washed with brine, dried with Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)c(OC)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(N)c2)c(OC)c1

Procedure:
Following a similar procedure to that described in Example (1b), 720 mg of isorner B of N-[1-(3,4-difluorophenyl)ethyl]-N-[(2,4-dimethoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 799 mg of nickel chloride hexahydrate, 254 mg of sodium borohydride and 80 ml of methanol were reacted, to obtain 580 mg of isomer B of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:12]2([OH:25])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:27][C:28](=[O:51])[C@H:29]([C@@H:48]([CH3:50])O)[NH:30]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:12]2([O:25][C@H:48]([CH3:50])[C@@H:29]([C:28]([OH:51])=[O:27])[NH2:30])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2sccc2-c2ccccc2)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2sccc2-c2ccccc2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-phenylthien-2-yl)-9H-fluoren-9-ol and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[C:3]([O:11][Si:20]([CH3:22])([CH3:21])[CH3:19])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C#CCC(O)(CCCC)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 4.99 g. of 4-trifluoromethyl-4-hydroxy-1-octyne and 5.65 g. of imidazole in 28 ml. of dry dimethylformamide, under argon, is cooled in an ice bath and then treated with 5.2 ml. of trimethylsilyl chloride by dropwise addition over a period of about 20 minutes. After an additional 15 minutes at ice bath temperature, the reaction mixture is stirred at room temperature overnight. The mixture is then poured into approximately 150 ml. of hexane and washed with small portions of ice cold water and saturated saline solution. The solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[NH2:17][C:18]1[N:19]=[C:20]([CH3:33])[C:21]2[CH:27]=[C:26]([C:28]#[N:29])[C:25](=[O:30])[N:24]([CH2:31][CH3:32])[C:22]=2[N:23]=1>C1(C)C=CC=CC=1>[NH2:17][C:18]1[N:19]=[C:20]([CH3:33])[C:21]2[CH:27]=[C:26]([C:28]3[NH:16][N:15]=[N:14][N:29]=3)[C:25](=[O:30])[N:24]([CH2:31][CH3:32])[C:22]=2[N:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCn1c(=O)c(C#N)cc2c(C)nc(N)nc21
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(-c2nnn[nH]2)cc2c(C)nc(N)nc21
Temperature: 140 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
Tributyltin azide (660 μL, 2.41 mmol) was added to a flask charged with 2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.184 g, 0.803 mmol) in anhydrous toluene (5.0 mL). The reaction was fitted with a reflux condenser and heated to 140° C. under a nitrogen atmosphere. After 20 h, the reaction was cooled to room temperature and the precipitate collected by vacuum filtration and washed with absolute ethanol to give 2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (98 mg, 45% yield) as a light brown solid: 1H NMR (400 MHz, 20% DCl in D2O): δ 6.97 (s, 1H), 2.42 (q, J=7.2 Hz, 2H), 0.953 (s, 3H), −0.73 (t, J=7.2 Hz, 3H); MS (EI) for C11H11N8O: 271.0 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.CS(Cl)(=O)=O.[C:24]([O-])(=[S:26])[CH3:25].[K+]>ClCCl.CC(C)=O.C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][O:6][C:24](=[S:26])[CH3:25]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=S)OCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 4,4,5,5,5-pentafluoropentanol (23.2 g, 130 mmol) in dry dichloromethane (100 ml) were added dropwise at 0° C. triethylamine (27 g, 267 mmol) and methanesulfonylchloride (30 g, 262 mmol), which was then warmed to room temperature over 12 hours. After the reaction was completed, the mixture was poured into ice-water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product (33.9 g). This crude product thus obtained was then dissolved in acetone (500 ml), potassium thioacetate (18 g, 158 mmol) was added thereto at room temperature, and the resulting mixture was stirred for 12 hours. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 4,4,5,5,5-pentafluoropentylthioacetate (15.8 g, yield 51%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([CH3:13])[C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[Cl:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]2[O:6][CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[C:8]=2[CH:9]=1
Reactant: Cc1cc(Cl)cc2c1OCCCC2N
Reactant: CS(=O)(=O)Cl
Product: Cc1cc(Cl)cc2c1OCCCC2NS(C)(=O)=O

Procedure:
0.6 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine (Example 10b) were reacted with methanesulfonyl chloride analogously to Example 10c. 0.6 g of 7-chloro-9-methyl-5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 154-156° C. By subsequent alkylation with butyl iodide analogously to Example 11, 0.6 g of 5-(N-butyl-N-methylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 106-110° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][Si](C(C)(C)C)(C)C.[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22][CH2:21]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:6][C:5]1[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=1)[CH2:2][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22][CH2:21]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Reactant: COC(=O)[C@H]1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)[C@H]1c2ccc(OCc3cccc(O)c3)cc2CCN1C(=O)OC(C)(C)C

Procedure:
Example 4 was synthesized from (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane and (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate using a similar procedure as described in procedure 2, followed by tetrabutylammonium fluoride deprotection. HPLC retention time (Method c)=3.75 min. LC/MS (ESI) (M+H)+=436.20. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 4H), 1.49 (s, 5H), 2.73-2.99 (m, 2H), 3.62-3.83 (m, 2H), 3.69 (s, 3H), 5.00 (s, 2H), 5.12 (brs, 1H), 5.35 (d, J=14.65 Hz, 0.5H), 5.52 (d, J=7.07 Hz, 0.5H), 6.74-6.97 (m, 3H), 6.89-6.93 (m, 1H), 6.96 (d, J=8.08 Hz, 1H), 7.23 (d, J=7.83 Hz, 1H), 7.37 (dd, J=8.59, 4.29 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2nc(C(C)(C)C)sc2cc1N=C=S
Solvent: CC(C)=O
Product: COc1cc2nc(C(C)(C)C)sc2cc1NC(=S)N1CCN(CCO)CC1
Reaction time: 2 h

Procedure:
21 g (0.076 mole) of 2-tert.-butyl-6-isothiocyano-5-methoxy-benzthiazole are dissolved in 400 ml of acetone and a solution of 12 g (0.092 mole) of N-(2-hydroxyethyl)-piperazine in 40 ml of acetone is added dropwise. The mixture is stirred for 2 hours, cooled to 0°, filtered and washed with acetone, then with ether and finally with petroleum ether. 2-tert.-butyl-5-methoxy-6-{[4-(2-hydroxyethyl)-piperazin-1-yl]-thiocarbonylamino}-benzthiazole having a melting point of 161°-162° is obtained.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.Cl>O>[CH:22]1([NH:25][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1NC1CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 71.2 %

Procedure:
To a solution of 2,6-difluoro-3-nitrobenzoic acid (1.0 g, 4.92 mmol) in IMS (5 mL) and water (5 mL) were added Et3N (1.23 mL, 8.86 mmol) and cyclopropylamine (360 μL, 5.17 mmol). The reaction mixture was stirred at RT for 28 h. The pH of the solution was adjusted to 1 by addition of 1M aqueous HCl. A precipitate formed and this solid was collected by filtration, washing with water to afford the title compound (841 mg, 71%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.78 (1H, s), 8.28 (1H, dd, J=9.45, 5.85 Hz), 6.49 (1H, m), 2.84 (1H, m), 0.85 (2H, m), 0.68 (2H, m)
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:25][S:26][CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][S:26][CH3:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CSCCCl
Reactant: C/C(=C\c1ccc(O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 74.4 %

Procedure:
A mixture of 6 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, 4.8 g of 2-chloroethyl methyl sulphide and 10.5 g finely powdered potassium carbonate in 100 ml of dimethylformamide is heated to 100° for 20 hours. The cooled reaction mixture is diluted with water and extracted several times with ethyl acetate. The crystalline residue obtained after drying and evaporating the organic phase is recrystallized from hexane and gives 5.5 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl sulphide in colourless crystals, melting point 94°-96°.
Reaction SMILES: C(O[C:4](=[O:25])[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=1[CH3:24])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:16])[CH3:15])[CH:9]=1)C>O>[Br:23][C:19]1[C:18]([CH3:24])=[C:17]([C:5]2[C:4](=[O:25])[C:13]3[C:8](=[CH:9][C:10]([N:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=CNc1cccc(N(C)C)c1)c1cccc(Br)c1C
Solvent: O
Product: Cc1c(Br)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To 2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino)-acrylic acid ethyl ester (100 mg, 0.248 mmol) was added 4 g polyphosphoric acid. This stirred at 140° C. for 10 minutes. 50 ml water was added and the mixture was stirred. The resulting precipitate was filtered and washed with water. The filtrate was extracted with 10% methanol/dichloromethane solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was combined with the precipitate and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one (22 mg, 0.062 mmol). MS (ESI) 357.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[CH:4][C:3]=1[F:19].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:20]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:19])[CH:4]=2)[CH2:12]1)=[N+:21]=[N-:22]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 75 °C
Yield: 92.6 %

Procedure:
Methanesulfonic acid 3-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl ester (38.6 g, 111.9 mmol) was added to dimethyl formamide (100 ml) followed by addition of sodium azide (14.5 g, 223.8 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (200 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (31 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH2:15])=[O:14])=[CH:7]2.[Cl:18][CH:19](Cl)[C:20](=O)[CH3:21]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:18][CH2:19][C:20]1[N:15]=[C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:12][CH:11]=3)[O:14][CH:21]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1

Procedure:
5-trifluoromethoxy-1H-indole-2-carboxylic acid amide (4.5 g, 18.43 mmol) and dichloro acetone (3.5 g, 27.63 mmol) in toluene/DMF (5:1, 30 ml) were kept at reflux temperature for 24 h with continuous removal of water by applying a Dean-Stark trap (a water separator used in chemical reactions). After removal of solvents in vacuo, the residue was intensively shaken with water, the precipitate was isolated by filtration and washed with water and brine. After evaporation of the solvents in vacuo chromatography on silica gel (iso-hexanes/ethyl acetate 3:1) yielded 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole as off white solid. Yield 2.6 g (44%)
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2cccc(F)c2)ccc(F)c1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 2-[2,4-difluoro-3-[[6-fluoro-3-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenoxy]acetate (240 mg, 0.53 mmol, 1.0 eq) in a mixture of THF (2 mL) and MeOH (2 mL) was added NaOH (2M aqueous solution, 2 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 3 h. The THF and MeOH were evaporated in vacuo and the pH of the aqueous phase adjusted to pH 3 by addition of diluted HCl. The solid that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (150 mg, 68%).