Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)nc(Nc2ccccc2Cl)n1
Temperature: 20 °C
Yield: 97.6 %

Procedure:
272.0 g of cyanuric chloride (content >99%), 1,000 ml of water and 275 ml of toluene are mixed at 5° C. The aqueous phase thereby assumes a pH value of 3.5. 188.2 g of o-chloroaniline are added in the course of 30 minutes without cooling or heating the mixture, whereupon the temperature rises to 30° C. A pH value of 7 is then established in the course of 1 hour by addition of 45% strength sodium hydroxide solution, whereupon the temperature rises up to 55° C. The mixture is then cooled to 20° C. in the course of 15 minutes. The product is filtered off, washed salt-free with water and dried at 60° C. in a waterpump vacuum. 396.5 g of 2-(2-chlorophenylamino)-4,6-dichloro-s-triazine are obtained with a melting point of 159° C. and a content of 98.9%, which corresponds to a yield of 97.5% (based on 99 % pure cyanuric chloride).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=NC(C(F)(F)F)=C[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.I[C:60]1C=CC=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:60][CH:61]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-iodo-3-(trifluoromethyl)benzene.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[CH:11]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][C:17]=2[F:25])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH:11]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]3[O:10][C:4]4[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=4[N:2]=3)=[CH:18][C:17]=2[F:25])[CH2:12][CH2:13]1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(O)c1ccc(OCC2CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (5.00 g), 4-(cyclopropylmethoxy)-3-fluorobenzoic acid (5.91 g) and diisopropylethylamine (7.37 mL) in DMF (50 mL) was added HATU (11.8 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate. To a solution of the obtained solid, hexachloroethane (16.7 g) and triphenylphosphine (18.5 g) in acetonitrile (50 mL) was added triethylamine (11.8 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: NC1CCN(c2ccc(F)nc2)C1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CC[C@H](NCc3ccc(C(F)(F)F)cc3)C2)cn1
Reaction time: 18 h

Procedure:
Add 4-(trifluoromethyl)benzaldehyde (30 μL, 0.22 mmol) to a solution of 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.2 mmol) and triethylamine (90 μL, 0.66 mmol) in methanol (1 mL). Vortex the resulting mixture and allow to sit for 18 h. Add sodium borohydride (12-15 mg, 0.3-0.4 mmol). When the bubbling begins to subside, vortex and allow to sit for 1 h. Dilute the reaction mixture with methanol (2 mL) and pour onto a column of Dowex® 50Wx2 (H+ form). Rinse the column with methanol, elute the product with 5% triethylamine in methanol and concentrate. Redissolve the residue in methanol, dilute with acetonitrile and concentrate to dryness to give the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.N1C=CC=CC=1>[NH2:19][C:17]1[C:18]2[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)=[CH:11][N:12]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A solution of 5-(3-amino-4-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.124 mmol) in dichloromethane (1 ml) and pyridine (1 ml) was cooled to 0° C. and then treated with benzyl chloroformate (32 mg, 0.186 mmol) while maintaining a temperature of less than 5° C. The solution was stirred for another 1 hour at 0° C. then the solvents were removed under reduced pressure. Purification by preparative C-18 RP-HPLC then lyophilization provided benzyl N-[5-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg) as a white powder: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.1-7.4 (m, 8H), 6.2 (bs, 2H), 5.15 (s, 2H), 5.07 (m, 1H), 3.8 (s 3H), 1.6-2.2 (m, 8H), RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.63 min.; MS: MH+458.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](C(F)(F)F)=[CH:18][CH:17]=2)=[CH:12][N:11]=1)=[O:8])=[O:5].NC1C=NC(C2C=CC(C(F)(F)F)=CC=2)=CN=1.[Cl:47]C1C=CC=CC=1C(N=C=O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:47])=[CH:18][CH:17]=2)=[CH:12][N:11]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(Cl)cc2)cn1

Procedure:
2M. 1-(2-Chlorobenzoyl)-3-[5-(α,α,α-trifluoro-p-tolyl)-2-pyrazinyl]urea, having a melting point of about 213°-215° C., and weighing 0.6 g., from 0.6 g. of 2-amino-5-(α,α,α-trifluoro-p-tolyl)pyrazine and 0.55 g. of 2-chlorobenzoyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[N:33]([Si](C)(C)C)=[N+:34]=[N-:35].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([Cl:32])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[NH:35][N:34]=[N:33][N:31]=4)=[CH:26][C:24]=3[N:25]=2)=[C:17]([Cl:19])[CH:18]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2nc3cc(-c4nnn[nH]4)ccc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 76.9 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in toluene (5 mL), was added azidotrimethylsilane (Aldrich, 0.12 mL, 0.90 mmol) and dibutyltin oxide (Aldrich, 11 mg, 0.045 mmol). The resulting mixture was heated at 90° C. overnight (15 hours). A 1M aqueous solution of HCl (50 mL) and ice was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 209 mg (77%) of product as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnn(C)c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cnn(C)c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (1-methyl-1H-pyrazol-4-yl)-acetic acid methyl ester [prepared by treatment of (1H-pyrazol-4-yl)-acetic acid methyl ester with NaH followed by MeI; used as obtained after aqueous workup] with heating for 15 days to afford the title compound as a tan solid (12 mg, 4%). LC/MS (Method B) 3.55 min, [M+1]+ 475.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH2:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:27][C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-t-butylbenzoic acid (1.15 g, 6.45 mmol), (R)—N-BOC-3-aminopiperadine (1.00 g, 4.99 mmol), BOP (3.42 g, 7.73 mmol), and N-methylmorpholine (2.5 mL, 22.7 mmol) in DMF (10 mL) was stirred at rt for 2 hr and then heated at 55° C. for 3 hr. It was then diluted with ethyl acetate (150 mL), washed sequentially with water (3×50 mL) and brine (50 mL), and dried over anhydrous MgSO4. Removal of solvent under vacuum provided a crude product of the titled compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Cl:16])[C:10]([CH3:15])([N+:12]([O-])=O)[CH3:11])=[CH:5][CH:4]=1.C(O)(=O)C.COCCOC>[H][H].[Pt](=O)=O>[ClH:16].[CH3:15][C:10]([NH2:12])([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: COCCOC
Solvent: CC(=O)O
Product: COc1ccc(CC(C)(C)N)cc1
Product: Cl
Reaction time: 4.5 h
Yield: 55.6 %

Procedure:
A mixture of 812 mg of 1-(4-methoxyphenyl)-1-chloro-2-methyl-2-nitropropane, 2 ml of acetic acid, 150 mg of platinum dioxide and 20 ml of 1,2-dimethoxyethane is stirred at 20° C. for 2 hours in hydrogen gas atmosphere under 70 atmospheres, and then at 45° C. for 4.5 hours under 68-65 atmospheres, and then at 80° C. for 14 hours under 68 atmospheres. After cooling, the reaction mixture is filtered to remove insoluble materials, and said insoluble materials are washed with ethanol and water, successively. The filtrate and the washing are combined, and the combined solution is evaporated to remove solvent. Cold 10% hydrochloric acid is added to the residue (brown oil), and the mixture is extracted with chloroform. The aqueous layer is alkalized with 10% sodium hydroxide under cooling, and then extracted with benzene. The extract is washed with water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. The residue (colorless oil, 460 mg) is dissolved in 2 ml of isopropylalcohol. 4 ml of ether containing hydrogen chloride (27 g/500 ml) are added to the isopropylalcohol solution, and said solution is allowed to stand. The crystalline precipitates are collected by filtration, washed with ether, and then recrystallized from isopropylalcohol. 400 mg of α,α-dimethyl-4-methoxyphenethylamine hydrochloride are thereby obtained as colorless plates.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=O)[CH3:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:20][C:17]1[S:16][C:15]([C:12](=[N:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH3:13])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(=O)c1ccc(C)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Yield: 87.5 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (4.0 q, 25 mmol), 2-acetyl-5-methylthiophene (4.4 g, 31 mmol), and p-toluenesulfonic acid (50 mg) in toluene (30 mL) was heated under reflux with azeotropic removal of water for 10 hours. Then the mixture was concentrated on a rotary evaporator, and the oily residue was distilled under reduced pressure to give 6.2 g (88%) of ketimine 12q as an oil (bp 128°-130° C./0.3 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][C:23]([CH3:25])=[CH2:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: C=C(C)CBr
Product: C=C(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromo-2-methylpropene according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-methylprop-1-en-3-yl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(OCC)c1nc(Cl)nc2ccsc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of Example 2 (3.0 g, 14.6 mmol) in 1,4-dioxane (200 mL) was added a solution of K2CO3 (4.0 g, 29.3 mmol) in water (40 mL). The almost clear solution was placed under nitrogen atmosphere and (1-Ethoxyvinyl)-tributylstannane (5.0 mL, 14.6 mmol) and PdCl2(PPh3)2 (500 mg, 0.731 mmol). The mixture was heated to 100° C. and stirred at 100° C. for 30 min under nitrogen atmosphere. After cooling to room temp. the 1,4-dioxane was removed i. vac. The residue was re-dissolved in DCM (100 mL) and water (50 mL) and transferred to a separating funnel. The aqueous layer was extracted with DCM (30 mL), the combined organic layers were washed with water (50 mL) and sat. brine (30 mL), dried over Na2SO4 and evaporated to dryness i. vac. The residue was purified by flash column chromatography (50 g SiO2 Isolute® pre-wetted with 1CV DCM) eluting with neat DCM collecting 12 mL fractions. Desired product eluted in fractions 10 to 20 with Rf=0.31 (DCM). By-products eluted in fractions 6 to 9 (Rf=0.59 in DCM) and fractions 21-31 ((Rf=0.14 in DCM). Fractions 10 to 20 were combined and evaporated to dryness i. vac. providing 2.28 g (65% yield) 2-chloro-4-(1′-ethoxy-vinyl)-thieno[3,2-d]pyrimidine as yellow powder of 95% purity.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:40]([CH2:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: NCCc1ccccn1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCc3ccccn3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-pyridin-2-ylethanamine (0.97 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.81 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([OH:30])(=O)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cs].CN(C=O)C.C(Cl)(=O)C([Cl:40])=O>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([Cl:40])(=[O:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cs]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Reaction time: 1 h

Procedure:
A suspension of the title D compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)benzenesulfonic acid, cesium salt (9.9 9, 20 mmol) in 200 mL of CH2Cl2 is treated with DMF (3.1 mL, 40 mmol), then oxalyl chloride (3.5 mL, 40 mmol) is added over 30 min at RT. The reaction mixture is stirred for 1 h further, then diluted with Et2O (200 mL) and washed with water and brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The product is washed with Et2O (5 mL) and dried in vacuo to afford 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)benzenesulfonyl chloride: NMR (CDCl3) 2.24 (s, 6H), 5.31 (s, 2H), 7.02 (dd, 1 H, J=8.7, 3.8), 7.10 (d, 1H, J=8.7), 7.32-7.47 (m, 4H), 7.52 (d, 2H, J=7.5), 8.05 (s, 2H).
Reaction SMILES: [OH-].[K+].C(OC([N:13]1[CH2:18][CH2:17][C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1.CO.C(Cl)(Cl)Cl>C(O)C>[C:24]1([C:16]2([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2)(N2CCCC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: c1ccc(C2(N3CCCC3)CCNCC2)cc1
Yield: 151.7 %

Procedure:
11 g of KOH were added to a solution of 7.3 g (1 equiv.) of benzyloxycarbonyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine in 100 ml of ethanol, and the reaction mixture was heated for 24 hours at reflux. The progress of the reaction was monitored by thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the solvent was distilled off completely, 100 ml of water were added to the residue, and extraction was carried out 3× with 100 ml of CHCl3. The combined organic phases were dried with Na2SO4. After removal of the solvent under reduced pressure, 7 g of crude product were obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[N:15][C:16]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CS(C)=O>[NH2:10][C:11]1[C:16]([C:17]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:25])=[N:15][C:14]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)=[O:31])=[CH:33][CH:34]=2)=[CH:13][N:12]=1
Reactant: CN(C)C1CCNCC1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(-c3cnc(N)c(C(=O)Nc4ccccc4)n3)cc2)CC1
Temperature: 38 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
N,N-dimethylpiperidin-4-amine (57.54 mg, 0.449 mmol) was weighed into a greenhouse tube and treated with a solution of 4-(5-amino-6-(phenylcarbamoyl)pyrazin-2-yl)benzoic acid (50 mg, 0.150 mmol), CDI (48.51 mg, 0.299 mmol) and DMAP (1.82 mg, 0.015 mmol) in DMSO (1 mL of a stock solution). DIPEA (78.2 uL, 0.449 mmol) was then added and the mixture stirred at 38° C. for 6 hours. The reaction mixture was filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (54.65, 80% Yield). (ES+) 445