Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.N1C=CC=CC=1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([C:31]([N:16]2[CH2:17][CH2:18][C@@:7]34[C:8]5[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=5[CH2:14][C@@H:15]2[C@:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Reactant: O=C(O)C1CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(C(=O)C1CCC1)CC3

Procedure:
To a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXI in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutylcarboxylic acid in 5 ml. of methylene chloride. After stirring for ten minutes, the reaction mixture was washed successively with cold dilute aqueous hydrochlorid acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na2SO4 and evaporation of the solvent, there was obtained 400 mg. of an oil which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to yield 320 mg. (61.6 %) of crystals which after recrystallization from methanol melted at 183°-85° C. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: O.Cl.[C:3]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][C:23]([O:32][CH2:33][CH2:34][OH:35])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:51](Cl)(=[O:53])[CH3:52].Cl>C(Cl)Cl>[ClH:42].[C:51]([O:35][CH2:34][CH2:33][O:32][C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][C:13]2([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:21][CH2:22]1)(=[O:53])[CH3:52]
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(OCCO)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCCOC1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 3 h

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 17 and 0.5 ml of triethylamine in 25 ml of DCM is cooled to 0-5° C., 0.085 ml of acetyl chloride is added and the mixture is stirred for 3 hours, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p.=105-107° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36])[CH3:31]>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[O:32][CH2:30][CH3:31])=[O:28])=[CH:22][CH:23]=1
Reactant: CCOc1ccccc1CN
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Reactant: O=C(Br)CBr
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(N(C)C)cc1

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[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][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>N1C=CC=CC=1>[F:2][C:3]([F:30])([F:29])[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][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:25])=[CH:22][CH:21]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 25.2 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N hydrochloric acid, and the organic layer separated, dried over magnesium sulfate and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1.[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[OH:10]/[N:9]=[C:8](\[Cl:15])/[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(trifluoromethoxy)benzaldehyde oxime (9.5 g, 46 mmol) in DMF (80 ml) was added N-chlorosuccinimide (8.0 g, 60 mmol) and the resulting mixture was stirred at RT for 5 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc, and washed with H2O, brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The solid residue was used without further purification for the following step. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=7.2 Hz, 2H), 7.13 (d, J=6.8 Hz, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl2 was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH4OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1.C(=O)=O.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S@:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4F)nc3)CC2)n1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@](C)=O)cc4F)nc3)CC2)n1
Yield: 20 %

Procedure:
The racemic sulfoxide 2-[2-fluoro-4-(methylsulfinyl)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (prepared as in Example 176, 195 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 280 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (39 mg) was isolated as an off-white solid with Tr of 16.69 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([CH3:22])=[CH:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[C:13]([CH3:22])=[CH:12][C:11]4=[O:23])[CH2:4][CH2:3]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
To 1.5 mL of dichloromethane solution containing 6.0 mg of 1-(2-(4-aminocyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one, 10 mg of molecular sieves 3A, 3.4 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 1.6 μL of acetic acid were added at room temperature, and stirred at the same temperature for 1.5 hours. To the reaction mixture, 6.0 mg of sodium triacetoxyborohydride was added, and stirred at the same temperature for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[eluent; chloroform: methanol=10:1], to give 5.5 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a yellow oil.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl.[OH2:16]>C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][C:9]=1[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:16]
Reactant: O
Reactant: COc1ccc(C)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C)cc1C(=O)c1ccccc1
Yield: 78 %

Procedure:
SnCl4 (47.5 ml, 0.41 mol) was added dropwise to a mixture of 4-methylanisol (100 g, 0.82 mol) and benzoyl (95.15 ml, 0.82 mol) in 500 ml of CH2Cl2 at 0° C. Once the addition is complete, it was allowed to react for 3-4 hours, allowing the mixture to reach room temperature. Once the reaction concluded, the mixture was cooled at 0° C., hydrolyzed with a mixture of concentrated HCl (41 ml) in H2O (376 ml), washed with 2×50 ml of NaOH (10%), dried and evaporated to give 140 g (78%) of the title compound in crystalline solid form.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N:7]1([CH:15]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14]CCCCCN1.C(#[N:25])C>>[CH2:22]([CH:15]1[N:7]2[C:1](=[O:5])[C:2](=[O:3])[N:25]=[C:14]2[CH2:17][CH2:16]1)[CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC#N
Product: CCCCCC1CCC2=NC(=O)C(=O)N21

Procedure:
Ex-31) The product of Example 31d is treated with oxalyl chloride and diazabicyclooctane in acetonitrile to give the title compound, which is purified by partition between water and EtOAc, and passage over a silica column.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH2:1])[CH3:7])([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: C[C@H](N)C(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](N)C(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (S)-3-amino-2-methylbutan-2-ol (4 g, 38.8 mmol) and imidazole (5.20 g, 77.7 mmol) in CH2Cl2 (50 mL) was added TBSCl (8.7 g, 57.7 mmol) at 0° C. The mixture was stirred overnight. The mixture was washed with brine. The organic phase was separated and concentrated to give (S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-amine (8.4 g, 100%), which was used for the next step without purification. 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.08 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 2.83 (q, 1H), 4.08 (brs, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][C@@H:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]1[OH:40]>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:30][C@@H:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@@H:32]2[OH:40])=[O:28])=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:11]=1[NH:12][N:13]1[CH:18]=[CH:17][C:16](=[O:19])[NH:15][C:14]1=[O:20]>C(O)(=O)C>[Br:1][C:17]1[C:16](=[O:19])[NH:15][C:14](=[O:20])[N:13]([NH:12][C:11]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:10]=2[Cl:9])[CH:18]=1
Reactant: O=c1ccn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(Nc2c(Cl)cc(Cl)cc2Cl)cc1Br
Temperature: 25 °C

Procedure:
An excess of N-bromosuccinimide in acetic acid is added to 1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione and the mixture is refluxed for 10 hours. It is cooled to RT and is then poured into ice and filtered to give 5-bromo-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[N:2].[C:25](Cl)(=[O:29])[CH2:26][CH2:27]C>>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:25]([CH2:26][CH3:27])=[O:29])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[N:2]
Reactant: CCCC(=O)Cl
Reactant: COc1cc(OC)cc(C(=O)Nc2sc3c(c2C#N)CCNC3)c1
Product: CCC(=O)C1NCCc2c1sc(NC(=O)c1cc(OC)cc(OC)c1)c2C#N

Procedure:
Prepared according to general procedure A starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3,5-dimethoxybenzamide (compound B1) and butyric acid chloride.
Reaction SMILES: FC1C=C(N[C:10]2[CH:14]=[C:13]([S:15][CH3:16])[S:12][C:11]=2[C:17]([NH2:19])=[NH:18])C=CC=1C.[F:20][C:21]1[CH:22]=[C:23](NC2C=C(C(OC)=S)SC=2C)[CH:24]=[CH:25][C:26]=1[CH3:27].C[Al](C)C.[Cl-].[NH4+:44]>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([NH:44][C:14]2[CH:10]=[C:11]([C:17]([NH2:19])=[NH:18])[S:12][C:13]=2[S:15][CH3:16])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: [NH4+]
Reactant: COC(=S)c1cc(Nc2ccc(C)c(F)c2)c(C)s1
Reactant: CSc1cc(Nc2ccc(C)c(F)c2)c(C(=N)N)s1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)N)cc1Nc1ccc(C)c(F)c1
Yield: 44 %

Procedure:
4-[(3-Fluoro-4-methylphenyl)amino -5-methylthiothiophene-2-carboxamidine: The same procedure as in Example 253, step (b) was followed using 103 mg (0.349 mmol) of methyl 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate (as prepared in previous step), 2 mL of trimethylaluminum (2.0 M in toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL of toluene, and purified on a 2-g silica SPE column with 5% MeOH-CH2Cl2 to afford 45 mg (44%) of the title compound as a yellow foam 1H-NMR (DMSO-d6; 400 MHz) δ 2.13 (s, 3H), 2.50 (s, 3H ), 6.70 (m, 2H), 7.10 (m, 1H), 7.98 (s, 1H), 8.09 (s, 1H), 9.16 (br s, 4H). Mass spectrum (ESI, m/z): Calcd. for C13H14FN3S2, 296.1 (M+H), found 296.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[O:7]1[CH2:8][CH2:9][O:10][C:5]2[CH:4]=[C:3]([CH2:2][C:13]#[N:14])[CH:12]=[CH:11][C:6]1=2
Reactant: ClCc1ccc2c(c1)OCCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL×4). The combined organic layers were washed with water (50 mL×2) and brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile as a yellow oil (10.2 g, 86%). 1H-NMR (300 MHz, CDCl3) δ 6.78-6.86 (m, 3 H), 4.25 (s, 4 H), 3.63 (s, 2 H).
Reaction SMILES: [C:1]([NH:6][NH2:7])(=O)[CH2:2][CH2:3][CH3:4].[NH:8]=[C:9]([CH2:15][CH2:16][CH3:17])C(OCC)=O.[CH3:18]O>>[CH2:2]([C:1]1[NH:6][N:7]=[C:9]([CH2:15][CH2:16][CH3:17])[N:8]=1)[CH2:3][CH2:4][CH3:18]
Reactant: CO
Reactant: CCCC(=N)C(=O)OCC
Reactant: CCCC(=O)NN
Product: CCCCc1nc(CCC)n[nH]1
Yield: 85 %

Procedure:
A 3.95 g (38.7 mmol) sample of butyric acid hydrazide (from Step 1 of Example 12) was dissolved in 30 mL of methanol and treated with 5.0 g (38.8 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux for 3 days and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (80:20) gave 5.51 g (85%) of 5-butyl-3-propyl-1H-1,2,4-triazole as a colorless solid: mp 48.5°-50.0° C.; NMR (CDCl3) δ 0.92 (t, J=7 Hz, 3H), 0.97 (t, J=7 Hz, 3H), 1.31-1.46 (m, 2H), 1.66-1.84 (m, 4H), 2.72 (t, J=7 Hz, 2H), 2.75 (t, J=7 Hz, 2H); MS (FAB) m/e (rel intensity) 168 (100), 166 (4), 152 (3), 138 (3), 125 (3); HRMS. Calcd for M+H: 168.1501. Found: 168.1534.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[NH2:23]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:23][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:21]([O:20][CH3:19])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCN(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε,Nε-dimethyl-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=123-126° C.). The reaction was monitored by tlc (Rf=0.22 in 10% MeOH/DCM+1% TEA) and the product was purified by silica gel column chromatography.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]1[N:17]([CH3:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[C:14]=1[CH:26]([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[N:17]([CH3:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:26]([CH3:28])[CH3:27])=[CH:6][CH:5]=1
Reactant: CC(C)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1c(COc2ccc(Cl)cc2)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a suspension of sodium hydride (0.023 g of a 50% dispersion in mineral oil) in DMF (2 mL) at 0° C. was added 4-chlorophenol (0.042 g). To this was added a solution of 5-bromomethyl-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.10 g) in DMF (1 mL) and the reaction mixture was allowed to stir at ambient temperature for 18 hours. The reaction was then diluted with water and EtOAc. The phases were separated and the aqueous was extracted with further EtOAc. The combined organic phases were washed with further brine and dried with sodium sulfate. Filtration and evaporation of the volatiles in vacuo and purification of the residue via ISCO Combiflash chromatography (using EtOAc/heptane) afforded the 5-(4-chloro-phenoxymethyl)-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.020 g) as a light yellow solid. MS (ESI+): 357.1 [M+H]+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(#N)C>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13]
Reactant: Cc1cccnc1
Reactant: CCC#CCCCCCCCCBr
Solvent: CC#N
Product: CCC#CCCCCCCCC[n+]1cccc(C)c1
Product: [Br-]
Yield: 70 %

Procedure:
12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 3-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (70%). 1HNMR (300 MHz, CDCl3, ppm), 9.42 (s, 1H), 9.24 (d, 1H), 8.24 (d, 1H), 8.00 (dd, 1H), 4.95 (t, 2H), 2.62 (s, 3H), 1.95-2.2 (m, 6H), 1.23-1.45 (br, 10H), 1.1 (t, 3H); 13CNMR, 145.29, 144.24, 141.98, 139.42, 127.51, 81.57, 79.26, 61.83, 31.90, 28.95, 28.92, 28.82, 28.62, 26.02, 18.72, 18.63, 14.38, 12.40.