Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C@@H:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[CH2:14][N:13]3[C:30](=[O:33])[C:31]=2[OH:32])=[O:9])=[CH:4][C:3]=1[CH3:36]>CO>[F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C@H:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[CH2:14][N:13]3[C:30](=[O:33])[C:31]=2[OH:32])=[O:9])=[CH:4][C:3]=1[CH3:36]
Reactant: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC(C)(C)CC[C@@H]3N(C)C(=O)C(=O)N(C)C)ccc1F
Solvent: CO
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC(C)(C)CC[C@H]3N(C)C(=O)C(=O)N(C)C)ccc1F

Procedure:
N-((10S)-2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-7,7-dimethyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-N,N′,N′-trimethylethanediamide. [α]D23° C.=−72.4° (c=0.5, MeOH); HRMS (ES+): 502.2481 (M+H); 1H NMR (400 MHz, CDCl3) δ 9.35 (br s, 3H), 7.2 (m, 2H), 6.9 (t, J=9 Hz, 1H), 5.34 (br s, 1H), 4.8 (d, J=14 Hz, 1H), 4.5 (m, 2H), 4.5 (m, 2H), 3.3 (d, J=14 Hz, 1H), 3.0 (s, 3H), 2.98, (s, 3H), 2.96 (s, 3H), 2.2 (s, 3H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (s, 2H), 1.12 (s, 3H), 0.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[F:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:29][CH:26]1[CH2:25][CH2:24][CH:23]([CH2:22][N:19]2[CH2:20][CH2:21][C@@H:17]([F:16])[CH2:18]2)[CH2:28][CH2:27]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: NC1CCC(CN2CC[C@@H](F)C2)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Yield: 30.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (240 mg, 1.0 mmol) was reacted with 4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexanamine (100 mg, 0.5 mmol) to afford the product (61 mg, 15%) as a brown solid: ESI MS m/z 405 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](OCC)=[O:9])([O-])=O.C(O)(=O)C.C(OCC)(=O)C>[Fe].O>[O:9]=[C:8]1[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][C:5]2[C:4](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:1]1
Reactant: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2[nH]c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
29.0 g (0.21 mol) of diethyl 2-(2-nitrobenzylidene)malonate was added to 100 mL of acetic acid at room temperature, and the mixture was heated to 80° C. 37.0 g (0.66 mol) of an iron powder was slowly added to the above mixture, and thus the reaction temperature increased to 100° C. After the reaction temperature decreased, the reaction was carried out at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. Insoluble materials were filtered off, and the filtrate was neutralized by adding sodium hydrogen carbonate. A solid precipitated therefrom was separated by filtration, and this solid was dissolved in ethyl acetate. The filtrate was further extracted with ethyl acetate, and the extract was combined with the solution mentioned above. This solution was washed with citric acid and water in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 13.6 g (yield: 63%) of the title compound was obtained as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:37]1[C:45]2[C:40](=[C:41](B3OC(C)(C)C(C)(C)O3)[C:42]([F:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)(C(C)(C)C)(C)C>>[F:46][C:42]1[C:41]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([C:12]([N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]4)=[O:13])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][CH:38]=[CH:39]2
Reactant: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)(O)C1CCN(C(=O)c2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (88 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to yield 41.5 mg 118 following reverse phase HPLC purification. MS (Q1) 519.2 (M)+
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[S:11](Cl)(=[O:14])(=[O:13])[NH2:12].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(OS(N)(=O)=O)c1
Temperature: 15 °C

Procedure:
A solution of 3-dimethylaminophenol (6.90 g, 0.05 mole) in 30 ml of acetonitrile was added in 13 minutes to a chilled (15° C.) stirred solution of 0.10 mole sulfamoyl chloride (Preparation 19) in 30 ml of acetonitrile. This was followed by the addition of 14 ml (0.10 mole) of triethylamine. The resultant mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (~60 ml) and then extracted twice with sodium bicarbonate solution. The aqueous layers were back extracted with 1:1 ethyl acetate/acetonitrile once. The organic layers were combined, dried over sodium sulfate, charcoaled, filtered, and evaporated to a black oil weighing 7.57 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].CO.[CH2:18](Cl)Cl.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:18][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([C:8]#[N:9])=[CH:7][C:2]=1[Cl:1]
Reactant: ClCCl
Reactant: COc1cc(CC(=O)O)c(Cl)cc1C#N
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1cc(OC)c(C#N)cc1Cl

Procedure:
(2-Chloro-4-cyano-5-methoxyphenyl)acetic acid (545 mg, 2.4 mmol) was taken up in 1:1 MeOH:DCM (50 mL) and excess 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted, the excess was quenched with acetic acid and the solution was concentrated in vacuo. Flash chromatography (10-50% ethyl acetate/hexanes) gave the title ester as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.703 (s, 3H), 3.767 (s, 2H), 3.897 (s, 3H), 6.896 (s, 1H), 7.526 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][N:28](O)[CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[C:10]3[C:9]4[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=4[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:5]=[CH:4][CH:3]=2)[CH2:27]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: O[C@H]1CCN(O)C1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (130 mg, 0.36 mmol) and (S)-3-hydroxypyrrolidinol (91 mg, 1.04 mmol) in N,N-dimethylacetamide (1.6 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a white waxy solid, which was used in the next step without further purification (140 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.C1C=CC=CC=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C(OCC)(=O)C.CN(C=O)C>[CH:33]1([NH:36][C:20]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)=[O:22])[CH2:35][CH2:34]1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.40 g (0.00128 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-picolinic acid was mixed with 0.3 g (0.00128×2.0 mol) thionyl chloride and then with about 10 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and, thereafter, mixed with methylene chloride and then with 0.18 g (0.00128×2.5 mol) of cyclopropyl amine, followed by stirring at room temperature for about 30 minutes. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, and concentrated. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9](=O)[NH:10][C@@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]=2[O:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:23][C:9]1[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C[C@@H]1NC(=O)c2ccccc2-c2c(C)noc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C[C@@H]1N=C(Cl)c2ccccc2-c2c(C)noc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of methyl 2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4754 g, 1.661 mmol) in CH2Cl2 (4 mL) was added phosphorus pentachloride (0.432 g, 2.075 mmol). The reaction mixture was stirred at room temperature for 1 h. To the mixture was added aqueous 10% Na2CO3 and stirred vigorously for 15 min. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated to give yellow foam after drying. The foam was filtered over a plug of silica and eluted with 20% EtOAc:80% Hexanes. The product methyl 2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4701 g, 1.543 mmol, 93% yield) was obtained as a white foam. LC/MS m/z 305 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH2:22][CH2:23]Cl)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([C:14]#[N:15])[CH2:23][CH2:22][N:20]([CH3:21])[CH2:19][CH2:18]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CN(CCCl)CCCl
Agent: Cl
Product: CN1CCC(C#N)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step 1b (350 mg, yield 32%). 1H NMR (300 MHz, CDCl3) δ 7.91-7.88 (d, J=8.6 Hz, 2H), 7.43-7.40 (d, J=8.6 Hz, 2H), 7.32 (s, 1H), 3.03-2.98 (m, 2H), 2.57-2.38 (m, 7H), 2.26-2.21 (m, 2H). MS (ESI) m/z: Calculated for C16H16ClN3S: 317.08. found: 318.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:17][C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1
Reactant: Clc1ccc(-c2ccc(Cl)c(Cl)c2)nn1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(Cl)c(Cl)c3)nn12

Procedure:
A mixture of 2.6 g. of 3-chloro-6-(3,4-dichlorophenyl)pyridazine and 1.8 g. of acetic acid hydrazide is heated in 50 ml. of n-butanol for 24 hrs. to give the product of the example.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24]1([NH2:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[C:24]1([NH:30][C:8](=[O:9])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Diphenylcarbamic chloride (23 g, 0.1 mol, Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) was added to a solution of 10.1 g of triethylamine and 9.3 g (0.1 mol) of benzeneamine in 150 ml of chloroform. The resulting solution was heated under reflux overnight. The solution was cooled to room temperature and washed three times with 100-ml portions of brine solution, dried over anhydrous magnesium sulfate, and evaporated to give an off-white solid which was triturated with diethyl ether to give triphenylurea as a white solid, mp 136°-138° C.
Reaction SMILES: C([CH:5]([C:9]1[CH:18]=[CH:17][C:16]2[O:15][C:14]([CH3:20])([CH3:19])[CH:13]3[O:21][CH:12]3[C:11]=2[CH:10]=1)[C:6]([NH2:8])=[O:7])CCC.[NH3:22]>C(O)C>[NH2:22][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:5][C:6]([NH:8][CH2:6][CH2:5][CH2:9][CH3:10])=[O:7])[CH:10]=2)[O:15][C:14]([CH3:19])([CH3:20])[CH:13]1[OH:21]
Reactant: N
Reactant: CCCCC(C(N)=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Solvent: CCO
Product: CCCCNC(=O)Cc1ccc2c(c1)C(N)C(O)C(C)(C)O2

Procedure:
The n-butyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl) acetamide obtained above was immediately poured into a mixture of so much ethanol and 25%-strength aqueous ammonia solution (6:5 v/v) that a 0.2 M solution of the compound was obtained and was processed further in a manner corresponding to the procedure of Example 5E). 7.4 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-(n-butyl)acetamide was obtained, which was used without further purification for the subsequent reaction. The other regioisomer, 2-[3-amino-4-hydroxy-2,2-dimethylchromen-6-yl]-N-(n-butyl)acetamide, was not observed.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:17])([CH2:11]3)[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]#[N:35])=[O:28]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:11][C:10]([NH:17][CH2:26][C:27]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]#[N:35])=[O:28])([CH2:9]1)[CH:14]([CH2:13]3)[CH2:15]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a stirred mixture of the amine obtained in step IV (0.26 g, 0.96 mmol) and K2CO3 (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bath temperature was added under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.17 g) in 43% yield. m/z (M+1) 407; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.70-3.40 (m, 2H), 3.44 (s, 2H), 3.32 (t, J=6.7 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.93 (s, 2H), 2.41-2.10 (m, 8H), 1.90-1.46 (m, 7H), 1.43-1.35 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][Br:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 1-bromo-2-methyl-4-nitrobenzene (15 g, 79 mmol), benzoyl peroxide (2 g, 8 mmol) and NBS (17 g, 95 mmol) in CCl4 (150 mL) was stirred at reflux overnight. The mixture was cooled to room temperature and filtered, the filtrate was washed with water twice, dried over Na2SO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-nitrobenzene as light yellow oil (17 g, 69%). 1H NMR: 400 MHz CDCl3 δ 8.37-8.34 (m, 1H), 8.05-8.02 (m, 1H), 7.77-7.75 (m, 1H), 3.87 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:11]
Reactant: C1CCNCC1
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)C(CCC(=O)O)(CCC(=O)N1CCCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
0.3 g of racemic 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 1 ml of methanol and 0.5 ml of piperidine are placed at 60° C. for 15 hours in a round-bottomed flask. The reaction medium is diluted with 10 ml of water and acidified with 1 N HCl to pH 2-3. The white crystals formed are filtered, drained and then dried to give 0.3 g of the expected compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[CH:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reaction time: 24 h

Procedure:
The 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid ethyl ester 83 obtained above is mixed with a 2M-solution of KOH in EtOH (16.9 ml, 33.8 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and DCM. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([C:14](O)=[S:15])[C:11]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(OC(C)=O)=O>[CH2:1]([C:8]1[N:13]=[C:12]2[C:14]([O:19][C:17](=[O:18])[C:11]2=[CH:10][CH:9]=1)=[S:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)nc1C(O)=S
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=S)c2nc(Cc3ccccc3)ccc21

Procedure:
8.5 g (0.029 mol) 6-benzylthiopyridine-2,3-dicarboxylic acid are stirred into 150 ml acetanhydride 6 hours at 110° C. The substance thereby dissolves completely. The solvent is distilled off in a vacuum and the residue is employed in the next stage without further purification.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24][CH2:25][CH2:26]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCI
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Product: CCCCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using 1-iodo-n-nonane as the alkylating reagent the title compound was obtained as a colorless oil (70% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([N:32]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1>O1CCCC1.Cl.CO.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([NH2:32])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(-c2csc3c(N)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 35.4 %

Procedure:
N-(4-{4-Amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.058 g, 0.096 mmol) in tetrahydrofuran (2 mL) and aqueous hydrochloric acid (2 M, 0.225 mL) was stirred at ambient temperature for 15 h. The reaction mixture was diluted with methanol/dichloromethane (1:49, 50 mL), and the resulting solution was extracted with aqueous sodium carbonate (1 M, 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using a gradient of methanol/dichloromethane (1:19 to 1:9) as the mobile phase afforded the title compound (0.015 g, 0.034 mmol) as light brown flakes: 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 7.96 (d, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.39 (s, 1H), 7.35 (s, 1H), 7.33 (m, 1H), 7.17 (s, 1H), 7.15 (m, 1H), 7.06 (d, 1H), 4.77 (br, 2H), 4.71 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H); MS: (MH)+ 444.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CCOCC>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Clc1ccc(Cl)nc1
Solvent: O
Solvent: CCOCC
Product: NNc1ccc(Cl)cn1
Yield: 82.9 %

Procedure:
A mixture of 2,5-dichloropyridine (7.4 g, 50 mmol) and 50 ml of hydrazine hydrate (1 mol) was refluxed for 3 hours and the mixture was diluted with ether. The crystalline solid (1st crop) was filtered, the solid was washed with water; and the aqueous layer was extracted with ether (2×). The organic layer was partially concentrated in vacuo and filtered to yield an additional white solid (2nd crop). The concentration of the filtrate yielded more solid (third crop). The combined solid product was dried in vacuo to afford 5.95 g (82%) of 2-hydrazino-5-chloropyridine as a white solid, m.p. 116°-122° C.