Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (85.9 mg, 0.30 mmol), 2-amino-benzoic acid methyl ester (0.07 mL, 0.54 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (103.5 mg, 0.54 mmol) and 1-hydroxybenzotriazole (HOBt) (73.0 mg, 0.54 mmol) in DMF (3.6 mL) was added N,N-diisopropylethylamine, redistill (DIPEA) (69.8 mg, 0.10 mL, 0.54 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeEOH=12:3:1) to give 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (46.4 mg, 3.69% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[CH:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[S:12][C:10]3[C:9]([N:14]=2)=[CH:8][CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=4)=[O:31])[CH:23]=[CH:22][CH:21]=2)[N:11]=3)=[O:17])[CH2:20][CH2:19]1
Reactant: Cn1cncc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cncc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 88 %

Procedure:
In the same manner as in Example 101-4 and using N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (124 mg, 0.280 mmol), 1-methyl-1H-imidazole-5-carboxylic acid (71.9 mg, 0.570 mmol), HATU (260 mg, 0.684 mmol), N,N-diisopropylethylamine (298 μL, 1.71 mmol) and N,N-dimethylformamide (4 mL) as starting materials, the title compound (107 mg, 65%) was obtained as a white solid.
Reaction SMILES: Cl.CS[C:4]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:5]([OH:7])=[O:6]>[Zn].O>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:4]([CH3:8])[C:5]([OH:7])=[O:6]
Reactant: CSC(C)(C(=O)O)c1cccs1
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CC(C(=O)O)c1cccs1
Reaction time: 0.67 h
Yield: 58.5 %

Procedure:
Zinc powder (150 mg), 2 ml of conc. hydrochloric acid and 1 ml of water were added to 542 mg of α-methylthio-α-(2-thienyl)propionic acid, and the mixture was stirred at the refluxing temperature for 40 minutes. After cooling, it was extracted three times with 10 ml of diethyl ether. The organic layer was washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to short-path distillation (bath temperature 140°-160° C./12 mmHg) to afford 245 mg of α-(2-thienyl)propionic acid in a yield of 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
2-(1-(2-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (40 mg, 0.1 mmol) was reacted with 2-(methylsulfonyl)ethanamine to provide 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 134. LC/MS (ESI+): m/z 514 (M+H). 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.56 (s, 0H), 8.20 (s, 1H), 7.94 (s, 1H), 7.73 (d, J=7.0, 1H), 7.71-7.52 (m, 3H), 7.43 (s, 1H), 7.36 (d, J=8.9, 1H), 4.48 (d, J=6.6, 3H), 3.73-3.58 (m, 2H), 3.02 (s, 3H)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22]Cl)[CH:5]=1)[CH:2]=[CH2:3].[I-].[Na+].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: CCNCC
Reactant: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCl)c1
Agent: [I-]
Agent: [Na+]
Product: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCN(CC)CC)c1

Procedure:
A mixture was prepared by mixing 0.5 g of 4-allyl-2-[5allyl-2-(2-chloroethoxy)phenyl]phenol and 1.5 g of sodium iodide with 20 ml of acetonitryl. The mixture was refluxed by heating for 4 hours with stirring, 1 ml of diethylamine was added thereinto, refluxed for 3 hours with stirring and concentrated. The concentrate, wherein water solution of sodium hydrogencarbonate was added, was extracted with chloroform, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (dichloromethane:methanol=30:1) to yield 0.3 g of 4-allyl-2-{5-allyl-2-[2- (N, N-diethyl-amino)ethoxy]phenyl}phenol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3C[C@H](NC(=O)CO)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)C3C=CC=CC=3)[N:8]=2)[CH:6]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H:56]([NH:58][C:59]([CH2:61][O:62]C(=O)C)=[O:60])[C@@H:55](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH2:56]([NH:58][C:59]([C@@H:61]1[C@@H:18]([OH:26])[C@@H:17]([OH:27])[C@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:5]2[CH:6]=[C:2]([NH2:1])[N:3]=[CH:4]2)=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:62]1)=[O:60])[CH3:55]
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc(N)c4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU), by substituting (2S,3S,4R,5R)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide (Intermediate ZY) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in step ZU1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 130 °C
Yield: 107.9 %

Procedure:
To a solution of 3-chloro-5-(trifluoromethyl)phenol (2 g, 10.18 mmol) and 4-fluorobenzaldehyde (1.201 ml, 11.19 mmol) in DMF (30 mL), was added K2CO3 (2.109 g, 15.26 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.3 g, 10.98 mmol, 108% yield) as a brown oil. LCMS: rt=3.89 min, [M+H+]=301
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Yield: 94.1 %

Procedure:
A mixture of 9.7 g (37 mmol) of the above ester and 200 ml of 1 N sodium hydroxide is heated on the steam bath for 11/4 hours. The resulting suspension is poured over ice and acidified with 250 ml of 1 N hydrochloric acid. The solid is collected by filtration and washed with water and ethanol to give 8.15 g of the title acid, mp>310°.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>N1C=CC=CC=1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:19]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)=[CH:22][CH:23]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of anthranilic acid (34.3 g, 250 mmol) in pyridine (400 mL) was added 4-tert-butylbenzoyl chloride (94 mL, 500 mL) dropwise via an addition funnel. After stirring for 12 h, the solution was poured onto a slurry of ice and 2 N aqueous hydrochloric acid (100 mL). The mixture was extracted with dichloromethane and the organic extract was concentrated in vacuo. The residue was dissolved in fresh dichloromethane, washed once with 2 N aqueous hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with saturated aqueous sodium bicarbonate solution, three times with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was crystallized from ether/hexanes to give an initial crop of 15.2 g (22%) of the title compound as an off-white solid, followed by additional crops totalling 16.9 g (24%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(CO)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
To a solution of [8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-5-yl]methanol (163 mg, 0.426 mmol) and triethylamine (0.48 mL, 3.44 mmol) in dimethylsulfoxide (5.0 mL) was added sulfur trioxide-pyridine complex (0.44 g, 2.76 mmol) at room temperature. The mixture was stirred at room temperature for 24 hr. Aqueous sodium hydrogen carbonate was added dropwise to the reaction mixture at room temperature. The precipitated solid was collected by filtration. The solid was washed with water, 2-propanol and diisopropyl ether to give the title compound (140.8 mg, 0.37 mmol, 87%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.4 g, 12.33 mmol) in CH2Cl2 (100 ml) was added Dess-Martin periodinane (5.75 g, 13.56 mmol). The reaction was stirred 1 hr, then diluted with EtOAc (600 mL) and washed with saturated aqueous NaHCO3 (200 mL). The organic layer was then dried (NaHSO4), filtered, and concentrated. The residue was triturate with Et2O, stirring vigorously for 30 min, collecting solids by vacuum. The semi-pure product was purified by flash silica gel column and eluted with 10-20% EtOAc in hexanes, affording the product, ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (3.5 g, 8.92 mmol, 72.4% yield) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.89-7.86 (m, 1H), 7.78-7.73 (m, 1H), 7.45-7.41 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 2.63 (s, 3H), 2.53 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LCMS (M+H)=392.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:18]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1c(C(=O)O)cc2cc(C(=O)O)ccc21
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Sodium hydride (60% suspension, 125 mg, 5 mmol) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid (525 mg, 2 mmol) in dry DMF (10 mL) and maintained at ambient temperature for 1 hour. The reaction was cooled to 0° C. and then octyl bromide (1.5 mL, 13 mmol) was added. After 3 days the reaction was quenched by addition of 5% aqueous NH4Cl. The mixture was concentrated to dryness and then purified on a silica gel column using toluene. The product was then dissolved in 30 mL ethanol and 10 mL of 2 M NaOH was added. The solution was heated at 55° C. for 2 days. The ethanol was removed in vacuo and the resulting aqueous solution was acidified with 0.01 M HCl to pH 3. The resulting precipitate was filtered and rinsed twice with water. The isolated product was dried by evaporation from absolute ethanol (3×) to give 460 mg (73%) of 84.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:20]#[C:21][CH3:22])[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[I-].[NH2:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Br:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:22])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1
Reactant: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.8 %

Procedure:
A mixture of 3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (0.514 g, 1.29 mmol), 1-aminopyridinium iodide (0.343 g, 1.54 mmol) and potassium carbonate (0.231 g, 1.67 mmol) in N,N-dimethylformamide (8.0 mL, 1.0E2 mmol) was stirred at rt for 29 hours. The mixture was quenched with ice water (80 mL) then extracted with EtOAc 3 times. The combined EtOAc solution was washed with water, brine, dried over Na2SO4, filtered and purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexane) to afford a solid product. (0.410 g, 64.8% yield). LCMS: (FA) ES+ 491, 493. 1H NMR (400 MHz, CDCl3) δ: 8.43-8.46 (m, 2H), 8.32 (s, 1H), 7.39-7.42 (m, 1H), 6.90-6.93 (m, 1H), 5.57 (m, 2H), 3.72-3.76 (m, 2H), 2.76 (s, 3H), 0.96-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[CH2:6][C:5]2([CH3:22])[CH3:21]>[Fe].C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:22])[CH3:21]
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(Cl)cc21
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Yield: 95.9 %

Procedure:
Iron powder (43.0 g, 762 mmol), ethanol/water (3:1, 720 ml) and 6-chloro-4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (24.1 g, 76 mmol) were heated to reflux for 2 h. iron powder was filtered and the solvent was removed to afford 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as yellow solid (20.9 g, yield: 90%).
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCOC(=O)NC
Reactant: ClSCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)N(C)SCl
Temperature: 5 °C
Reaction time: 2.3 h
Yield: 101.3 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 97.4 g (0.4 mole) of n-dodecyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 150 ml of methylene chloride. The addition took 2.3 hr while the temperature was maintained at -10° to 5° C. After stirring for one additional hour at 5° C. the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Triethylamine hydrochloride was removed by extracting the product into 200 ml of hexane. After filtration, the hexane solution was concentrated to give 125.6 g n-dodecyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:3])[CH3:2].Cl[CH2:15][CH:16]1[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH:16]2[O:17][CH2:18]2)=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(=O)Oc1ccc(O)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1ccc(OCC2CO2)c(C)c1C

Procedure:
Using 4.30 g of 4-acetoxy-2,3-dimethylphenol, 4.6 ml of chloromethyloxirane, 3.30 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 6.05 g of 1-(4-acetoxy-2,3-dimethylphenoxy)-2,3-epoxypropane as brown oil. Using the epoxy compound thus obtained, 4.60 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis and workup followed by conversion to hydrochloride with 2N HCl, recrystallization from methanol gave 2.55 g of white crystals, m.p. 228-230° C. (decomp.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21])(C)(C)C.CCN(CC)CC.[CH2:37]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][N:38]1C(OC(C)(C)C)=O>CS(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][C:25]([N:43]2[CH2:44][CH2:45][C:40]3([CH2:37][NH:38][CH2:39]3)[CH2:41][CH2:42]2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC3(CC2)CNC3)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
tert-Butyl[2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate F (20 mg, 0.088 mmol) was dissolved in 1 mL of DMSO and treated with Et3N(0.010 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.047 mmol). The mixture was stirred at 90° C. for 18 h, partitioned between EtOAc and saturated NaHCO3, dried (MgSO4), filtered and concentrated), concentrated and the residue was purified by chromatography on SiO2 (EtOAc/CH2Cl2, 0% to 100%). The residue was dissolved in 1 mL of 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Neutralization with EtOAc/sat'd NaHCO3 extraction and drying (MgSO4) gave desired product, N-[2-amino-5-(2-thienyl)phenyl]-6-(2,7-diazaspiro[3.5]non-7-yl)nicotinamide, which was confirmed by MS (ESI+): cal'd [M+H]+ 420.2, obs'd 420.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.C([O-])(=O)C.[K+].[Br:26]Br>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[C:15]([Br:26])[CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: CCNc1ncccc1C(=O)Nc1ccc(Cl)nc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ncc(Br)cc1C(=O)Nc1ccc(Cl)nc1Cl
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a solution of N-(2,6-dichloro-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (7.4 g, 24 mmol) and potassium acetate (2.8 g, 28 mmol) in 90 mL of acetic acid was added bromine (1.2 mL, 23 mmol). After 15 min, the reaction mixture was diluted with water and the precipitate was collected by suction filtration to give 8.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-:18].[Na+]>CS(C)=O>[ClH:2].[OH:18][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: CC(C)NCCS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)NCCS(=O)(=O)c1ccc(O)cc1

Procedure:
A solution of N-[2-[(4-chlorophenyl)sulfonyl]ethyl]-1-methylethanamine hydrochloride and sodium hydroxide in 500 ml of dimethyl sulfoxide is heated at 95° C. for 2 hrs with stirring. The solvent is removed by rotary evaporation (vacuum pump) and the residue is partitioned between water (pH adjusted to 7 by the addition of dilute hydrochloric acid) and chloroform. The chloroform is removed and the residue is converted to the hydrochloride salt with ethereal hydrogen chloride. The salt is then recrystallized from methanol-diethyl ether to give crystalline title compound.