Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH:10]([O-])([O-])[O:11]C.[C:15]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)C>[CH3:15][O:9][CH:8]([O:11][CH3:10])[C:6]1[O:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(OC)c1ccc(CO)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.8 g of 5-hydroxymethyl-2-furaldehyde was dissolved in 70 ml of methanol, and 14.7 ml of methyl orthoformate and 170 mg of pyridinium p-toluenesulfonate were added. After the mixture was stirred at room temperature for 2 hours, 350 mg of sodium bicarbonate was added . The solution was stirred at room temperature for 30 minutes, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner to give 21.6 g of 5-hydroxymethyl-2-furaldehyde dimethylacetal as a pale brown oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1>CC(N(C)C)=O>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([F:19])[CH:13]=[C:12]([Br:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a stirred solution of benzyl alcohol (3.86 g, 20 mmol) in DMA (30 ml), NaH(60% dispersion in oil, 0.80 g, 20 mmol) was drop wisely added. After one hour, 1-bromo-3,5-difluorobenzen (3.86 g, 20 mmol) was added at such a rate to maintain the temperature no more than 40° C. The mixture was stirred at ambient temperature overnight. The reaction was quenched by water and extracted with EtOAc. It was purified via flash chromatography and gave the product (4.17 g, 74%) as colorless oil. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.41-7.43 (m, 5H), 6.94 (m, 1H), 6.86 (dt, 1H), 6.63 (dt, 1H), 5.02 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 165.20, 161.89, 160.72, 160.56, 136.01, 128.94, 128.57, 127.77, 127.73, 122.99, 122.83, 114.58, 114.53, 112.18, 111.84, 102.29, 101.96, 70.76; 19F NMR (CDCl3, 282 MHz) δ-31129.40 (t, J=2583.12 Hz).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][N:7]1[C:20](=[O:21])[C:19]2[C:18](=[O:22])[C:17]3[CH:16]=[CH:15][C:14]([Cl:23])=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([OH:24])=[N:8]1>CN(C)C=O>[Cl:23][C:14]1[CH:15]=[CH:16][C:17]2[C:18](=[O:22])[C:19]3[C:20](=[O:21])[N:7]([CH2:6][CH2:5][S:2][CH3:1])[N:8]=[C:9]([OH:24])[C:10]=3[NH:11][C:12]=2[CH:13]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a suspension of sodium thiomethoxide (230 mg, 3.2 mM) in dimethylformamide (20 mL), was added in one portion 2-(2-bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.4 g, 1.08 mM) as a dry powder. This mixture was warmed to gentle reflux for about three hours. At this point the heat was removed and the reaction mixture was poured into ice cold 1.2N HCl (100 mL) and stirred about one hour. The resulting precipitate was vacuum filtered and washed with water and ether, then vacuum dried at 50° C. to yield 330 mg (91 %) of the title compound as an off-white powder. mp 275-277° C.; MS: 338(M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (B) (0.057 g, 0.366 mmol), DIEA (0.192 mL, 1.098 mmol), and 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.100 g, 0.366 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. under microwave irradiation for 2 h and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give a racemic mixture 4-amino-6-((1-(6-fluoro-1-(3-fluorophenyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.65 Hz, 3H) 5.56 (qd, J=6.91, 6.65 Hz, 1H) 6.93 (dd, J=9.00, 2.35 Hz, 1H) 7.08-7.15 (m, 1H) 7.17 (br. s., 2H) 7.31 (td, J=8.41, 2.15 Hz, 1H) 7.35-7.40 (m, 1H) 7.48 (d, J=9.59 Hz, 1H) 7.56 (td, J=8.12, 6.65 Hz, 1H) 7.69 (d, J=7.63 Hz, 1H) 7.73 (dd, J=8.80, 4.89 Hz, 1H) 7.86 (s, 1H); LC-MS (ESI) m/z 392.1 [M+H]+. The racemic mixture (0.085 g) was separated by chiral separation using SFC to give two fractions:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH3:34]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNCCO
Solvent: CC(=O)N(C)C
Product: CN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 495 (MH+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42].O>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH:19]2[C:18]3[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)[C:11](=[O:10])[N:20]2[C:41]([O:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:42])=[CH:28][CH:27]=1)#[N:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
N,N-Diisopropylethylamine (1.65 mL, 9.72 mmol) and 4-dimethylaminopyridine (59 mg, 0.49 mmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 1.00 g, 2.43 mmol) in dichloromethane (6 mL), and the mixture is cooled in an ice bath. A solution of 4-nitrophenyl chloroformate (540 mg, 2.67 mmol) in dichloromethane (2 mL) is added, and the mixture is warmed to room temperature. After 3 h another portion of 4-nitrophenyl chloroformate (980 mg, 4.86 mmol) and N,N-diisopropylethylamine (830 μL, 4.86 mmol) are added, and the mixture is stirred over night. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified twice by flash chromatography on silica (first purification: gradient cyclohexane/ethyl acetate 100:0 to 70:30, second purification: gradient cyclohexane/ethyl acetate 100:0 to 50:50). Yield: 374 mg; ESI mass spectrum [M+H]+=577, Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(#N)C>[Cl-:1].[N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:11][C:3]=1[CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1nc2cccnc2[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2nc3cccnc3[nH]2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
3.18 g of chloromethyl-3H-imidazo[4,5-b]pyridine (G. Cleve et al., Liebigs Ann. Chem. 1971, 747, 158-171) are suspended in 16 ml of N,N-dimethylformamide and 50 ml of acetonitrile. 4.98 g of triphenylphosphine are added and the mixture is heated to 100° C. for 3 h. The mixture is concentrated to dryness and the crude product purified by chromatography on silica gel (eluent: dichloromethane/methanol 10:1 to 8:1) to afford 3.15 g of the title compound as a beige, amorphous solid. M.p. 302° C. MS: 394.3 (M+). TLC: Rf=0.17-0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>O>[CH2:6]1[O:5][C:4]2[C:8](=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:2]([CH:3]=2)[C:1]([OH:12])=[O:11])[O:7]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 50 °C

Procedure:
30 g (0.18 mole) of piperonylic acid are added with care to 200 ml of nitric acid (d=1.42). After a first addition of 5 g, the reaction is started by heating and by vigorously stirring the reaction mixture at 50° C. The addition of the remaining 25 g is carried out in small fractions. At the end of the addition, the reaction mixture is left stirring for 2 hours. Then 200 ml of water are added, the insoluble reaction product is spun, washed with 100 ml of water and then dissolved in a saturated aqueous solution of sodium bicarbonate. The insoluble compounds are removed. The filtrate is acidified at 0° C. and the precipitate is collected and then spun, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.S(Cl)(Cl)=[O:25].C(N(CC)CC)C.[CH3:35][O:36][C:37](=[O:40])[CH2:38]S>C1(C)C=CC=CC=1>[CH3:35][O:36][C:37](=[O:40])[CH:38]([C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:20]=[CH:21][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)[CH3:19])[OH:25]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)Cl
Reactant: COC(=O)CS
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(O)C(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
36.8 g or 2-[4-(6-chlorobenzthiazolyloxy)-phenoxy]-propionyl chloride (prepared by reacting 35 g of the free acid with 13.1 g of thionyl chloride in 150 cc of toluene for 8 hours at 80° C.) are added to 150 cc of toluene and a mixture of 12.1 g of triethylamine and 10.6 g of thioglycolic acid methyl ester in 50 cc of toluene is added at 25° to 30° C. The reaction mixture is stirred for a further 2 hours at 50° to 60° C. The mixture is cooled to 25° C. and washed three times with 150 cc of water each. The toluene phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue has completely crystallized after 3 days, yielding 40.5 g (92.7% of theory) of 2-[4-(6-chloro-2-benzthiazolyloxy)-phenoxy]-propionyl-glycolic acid methyl ester. m.p. 104° to 106° C. ##STR13##
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(Cl)Cl>ClCCCl>[O:25]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of AlCl3 (2.036 g; 15.27 mmol) in anh. DCE (10 ml) was treated with commercially available 1,3,5-trimethoxybenzene (1.675 g; 9.96 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 4-chloro-4-oxobutanoate (1.000 g; 6.64 mmol) was then added, and the mixture was stirred at rt for 24 h. The resulting reaction mixture was poured onto crushed ice (30 g), and DCM (20 ml) was added. The separated aq. layer was further extracted with DCM (3×10 ml). The mixed organic layers were washed successively with water (15 ml) and brine (2×15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate as a colorless oil. LC-MS (conditions D): tR=0.88 min.; [M+H]+: 283.02 g/mol.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[CH2:5][CH2:6]1
Reactant: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)CC2)c1

Procedure:
A mixture of trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine (0.26 g, 0.91 mmol), 1-(3-trifluoromethyl-phenyl)-piperazine (0.21 g, 0.91 mmol), and potassium carbonate (0.21 g, 1.5 mmol) was heated in 10 mL refluxing acetonitrile for 18 hours. The reaction was diluted with methylene chloride, filtered, and the solvents were removed under reduced pressure. The residue was partitioned between chloroform and aqueous 2N sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. The resulting residue was recrystallized from acetonitrile to give the title compound; mp 167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][Cl:35])[CH2:28]2)=[CH:21][CH:20]=1>>[ClH:35].[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][N:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][N:9]3[C:8](=[O:12])[CH2:7][C:6]4[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:11][CH2:10]3)[CH2:28]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(CCN2CCCCC(CCl)C2)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1
Product: Cl

Procedure:
Prepared from 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and N-[2-(4-methoxy-phenyl)-ethyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].C(Cl)(=O)C([Cl:15])=O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: C=Cc1ccc(C(=O)Cl)cc1
Reaction time: 8 h

Procedure:
p-vinyl benzoic acid (10 g, 0.067 mole) is suspended in benzene (25 ml). Oxalyl chloride (25 g, 0.2 mole) is added. The mixture is stirred for 8 hours under argon atmosphere. Solvent and excess oxalyl chloride is removed in vacuo. The product is distilled in vactio to yield p-vinyl benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:25][N:26]([CH3:31])[S:27]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:4]2[S:5][C:6]([C:7](=[O:8])[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=3)=[C:2]([NH2:1])[N:3]=2)[CH2:20][CH2:21]1)(=[O:29])=[O:28]
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)c2sc(NC3CCN(S(=O)(=O)N(C)C)CC3)nc2N)cc1F
Yield: 22 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone (0.08 g, 0.022 mmol) (Example 7)) was treated with dimethylsulfamoyl chloride in a manner similar to Example 9 except that diisopropylethylamine was additionally used as a catalyst and short plug of silica gel (ethyl acetate was used to pre-purify the sample to give 30 mg (22% yield) of 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid dimethylamide. 1H NMR (DMSO−d6, 300 MHz) δ1.51 (m, 2H, CH2), 1.97 (m, 2H, CH2), 2.77 (s, 6H, 2× NCH2), 2.99 (m, 2H, CH2), 3.52 (m, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 3.89 (s, 3H, OCH3), 7.9-8.5 (brd, 2H, 2NH), 8.71 (brd, 1H, NH). HRMS: (M+H)+: observed: 458.1331; calcd for 4581327.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:11](=[O:12])[C:10]([F:17])([F:16])[F:9])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cccnc1)C(F)(F)F
Yield: 93 %

Procedure:
22.87 g of 3-(aminomethyl)pyridine was dissolved in 100 ml dichloromethane and stirred with 50.4 ml ethyl trifluoroacetate and 29.5 ml triethylamine at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a residue, which was then recrystallized from ethyl acetate to provide N-(3-pyridylmethyl)trifluoroacetic acid amide (40.15 g, 93%).
Reaction SMILES: [NH2:1][C:2](=[S:19])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1.Br[CH2:21][C:22]([C:24]1[CH2:28][CH:27]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:26][N:25]=1)=O.C([O-])(=O)C.[Na+]>CO>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[CH:27]1[O:26][N:25]=[C:24]([C:22]2[N:1]=[C:2]([CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]3)[S:19][CH:21]=2)[CH2:28]1
Reactant: CCOC(=O)N1CCC(C(N)=S)CN1C(=O)OCC
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1C(=O)OCC
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A mixture of 1,2-diethyl 4-(aminothioxomethyl)tetrahydro-1,2-pyridazinedicarboxylate (i.e. the product of Step F) (2.58 g, 0.0089 mol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e the product of Step C) (2.63 g, 0.0086 mol) in methanol (20 mL) were carefully heated to 35° C. No exotherm was observed and the temperature was raised to between 45 to 50° C. and held at this temperature for 1 h. The reaction mixture was neutralised with aqueous sodium acetate (0.73 g in about 20 mL water). The reaction mixture was extracted with diethyl ether (3×), dried magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (4.18 g), which was used without purification.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](C(O)=O)([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:3].Cl>CN1C(=O)CCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:1]
Reactant: CC(C)Oc1cccc2c1CC(C(=O)O)(C(=O)O)C2
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cccc2c1CC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
A solution of 4-(2-propyl)oxyindan-2,2-dicarboxylic acid (11.5 g) in NMP (20 ml) was heated to 150° C. After a further 15 minutes, the solution was allowed to cool to room temperature, and was poured into aqueous hydrochloric acid (1500 ml, 1M). This mixture was extracted with ethyl acetate (2×500 ml) and a standard workup gave 4-(2-propyl)oxyindan-2-carboxylic acid (3.98 g) as a dark brown solid, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH:21]=O)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(O)(=O)C>C(Cl)(Cl)Cl.CO>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH2:21][NH:41][CH:38]4[CH2:40][CH2:39]4)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CNC1CC1
Yield: 11.5 %

Procedure:
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3083 mmol) was reacted with NaBH(OAc)3 (98 mg, 0.4624 mmol), Cyclopropylamine (0.032 mL, 0.462 mmol) and acetic acid (5 mL) at room temperature for 12 hours to afford the crude product. The reaction was monitored by TLC (5% methanol in chloroform). Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 13 mg of the product (11.6% yield).
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].C(#[N:35])C>>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31]([NH:35][C:5]1[N:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=[CH:2][CH:6]=1)=[O:32])[CH3:19]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC#N
Reactant: CCCCCCCCCCCn1ccc(N)n1
Product: CCCCCCCCCCCn1nccc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 3-amino-1-undecyl 1H pyrazole (3.7 g, 15.6 mmol) and 2,6-diisopropylphenylisocyanate (3.15 mL, 15.6 mmol) in acetonitrile (100 mL) was heated under reflux for 5 hours, then cooled (25° C.) and concentrated in vacuo to yield 7.0 g (100%) of the title compound as a yellow oil.