Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:23][C:22]1([CH3:24])[N:8]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[O:1]1
Reactant: COC(C)(C)OC
Reactant: N#Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To a stirred mixture of 2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbonitrile (1.2 g, 4.5 mmol) from Step 2 of this Example and 2,2-dimethoxypropane (4.7 g, 45 mmol) in 1,4-dioxane (30 mL) were added para-toluenesulfonic acid (89 mg, 0.5 mmol) and molecular sieves (4 Å) and the mixture was heated at reflux for 15 h. The mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography to afford 2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazole-6-carbonitrile (700 mg, 50%) as a white solid. LCMS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=[CH:7][C:6]1=2>C1(C)C=CC=CC=1>[OH:4][C:5]1([CH3:1])[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: C[Mg]Br
Reactant: O=C1CCCc2nc(OCc3ccccc3)ccc21
Solvent: Cc1ccccc1
Product: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 92 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 47 ml) was added dropwise to a solution of 5,6,7,8-tetrahydro-5-oxo-2(phenylmethoxy)quinoline (29.6 g) and toluene (1 l) at 0° C. The reaction mixture was allowed to warm to room temperature, with stirring. The redaction mixture was then quenched with saturated ammonium chloride solution, the layers were separate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to provide 31.7 g (92.0%) of product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1C=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Nc1cc(N)c(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)cn1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:26])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].C1COCC1.O.[OH-].[Li+]>O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:26])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ncccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1ccc(-c2ncccn2)cc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (41 mg) in a 1:1 mixture of THF and water (2.25 mL) was added lithium hydroxide monohydrate and the reaction mixture was stirred for 20 hours at room temperature. After such time the THF was evaporated off in vacuo and the remaining aqueous phase was neutralized by addition of a 1N HCl solution. The resulting precipitate was then isolated by filtration, washed with water, and dried in vacuo to yield the title compound as a light yellow solid. MS (m/e): 354.1 (M+H−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[H-].[Na+].F[C:15]1[C:20]([F:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[C:20]([F:21])[CH:15]=2)[CH:7]=[N:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: COC(=O)c1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(Oc2ccc([N+](=O)[O-])c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To an ice bath cooled solution of 5-hydroxynicotinic acid methyl ester (5.00 g, 32.65 mmol) in DMF (20 mL) was added sodium hydride (0.78 g, 32.65 mmol). The reaction mixture was stirred at room temperature for 2 hours, and 2,3-difluoro-4-nitrobenzene (5.12 g, 29.68 mmol) was added, and the reaction mixture was stirred at room temperature. After 3 hours the solvent was removed under reduced pressure, and the residue was partitioned between EtOAC (300 mL) and H2O (150 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were dried over Na2SO4, filtered, and the filtrate removed under reduced pressure. The crude product was purified by column chromatography eluted with 50 to 75% EtOAc/Hex to give 2.4 g (28%) of 5-(4-nitro-3-fluorophenoxy)nicotinic acid methyl ester. 1H-NMR (CD3OD) δ 9.05 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.31 (dd, J=2.4, 10.5 Hz, 1H), 8.15-8.14 (m, 1H), 9.06 (dd, J=1.5, 2.1 Hz, 1H), 7.40 (dd, J=8.1, 9.0 Hz, 1H), 3.97 (s, 3H); MS LC-MS [M+H]+=293.1; RT=3.15 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=O)[O:6][N:5]=1.C(C1C=C(C=CC=1)C(OCC)=O)#C.C1C(=O)N(Cl)C(=O)C1.COCC=NO.[C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])(=[O:48])[CH3:47].[Li]>C(Cl)(Cl)Cl.N1C=CC=CC=1.CCN(CC)CC>[C:50]([O:49][C:46](=[O:48])[CH2:47][C:12]([C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([C:7]2[O:6][N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:8]=2)[CH:10]=1)=[O:14])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(=O)OC(C)(C)C
Reactant: COCc1cc(-c2cccc(C(=O)OC)c2)on1
Agent: C#Cc1cccc(C(=O)OCC)c1
Agent: COCC=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from methyl 3-(3-methoxymethyl-isoxazol-5-yl)-benzoate [prepared by reaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixture of NCS, 2-methoxyacetaldoxime [CAS-No. 71494-93-4], Et3N and cat. amount of pyridine in CHCl3 at 50° C. according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a light yellow liquid (1.548 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[C:15]([Br:20])[CH:14]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[Br:8].[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][C:4]2[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=2)[N:12]1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[C:15]([Br:20])[CH:14]=1
Reactant: S=C(Nc1ccc(Br)c(Br)c1)Nc1ccc(Br)c(Br)c1
Reactant: O=C(O)C#CC(=O)O
Product: O=C(O)C=C1SC(=Nc2ccc(Br)c(Br)c2)N(c2ccc(Br)c(Br)c2)C1=O
Yield: 13.1 %

Procedure:
Prepared by the method described in Example 21 from N,N'-bis(3,4-dibromophenyl)thiourea (13.7 g, 25 mmoles) and acetylenedicarboxylic acid (2.7 g, 25 mmoles). Recrystallization from methanol gave the product (2.1 g), mp 235°-237° C.
Reaction SMILES: Cl.C(O[C:5](=[NH:42])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[N:15]([CH:39]=[CH:40][N:41]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[C:20]=3[CH3:38])[N:18]=2)=[CH:8][CH:7]=1)C.[CH2:43](N)[CH2:44][NH2:45]>CO>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]3[N:18]=[C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([C:5]5[NH:45][CH2:44][CH2:43][N:42]=5)=[CH:11][CH:10]=4)[C:14]4[N:15]([CH:39]=[CH:40][N:41]=4)[CH:16]=3)[C:20]=2[CH3:38])=[O:37])=[CH:32][CH:31]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn3ccnc23)cc1
Agent: Cl
Solvent: CO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C3=NCCN3)cc2)n1
Temperature: 60 °C
Yield: 35.4 %

Procedure:
4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidic acid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved in methanol (5 mL) in a glass pressure reaction vessel, and ethylenediamine (100 mg; excess) is added. The reaction is heated to 60° C. for 16 hr then concentrated in vacuo. The oil is dissolved in 2 mL CH2Cl2 and diethyl ether (20 mL) is added to precipitate out 4-tert-butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide as a light tan solid (100 mg). Gradient silica flash chromatography using (90:9:1) (CH2Cl2:methanol:ammonium hydroxide) as the eluent provides the pure material as a white solid (50 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:17].Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=1)(=[O:21])=[O:20]>C1COCC1>[C:9]([C:5]1[CH:4]=[C:3]([I:17])[C:2]([O:1][S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=2)(=[O:21])=[O:20])=[C:7]([I:8])[CH:6]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(c1ccccc1)c1cc(I)c(O)c(I)c1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(I)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(I)c1
Yield: 30 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (4-hydroxy-3,5-diiodo-phenyl)-phenyl-methanone (0.346 g, 0.768 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.928 g, 3.92 mmol) in THF. Purification On Biotage KP-Sil, eluting with 10% MeOH/CHCl3 followed by crystallization from EtOAc/hexane gave 0.15 g (30%) of the title compound as an orange solid, mp 190° C. 1H NMR (DMSO-d6) δ 7.22-7.35 (m, 2H), 7.58 (t, 2H), 7.69-7.75 (m, 3H), 7.95 (d, 1H), 8.10 (s, 2H). IR (KBr) 3400, 3100, 1660, 1280 and 1180 cm-1. mass spectrum (+FAB) m/z 651 (M+H). Anal. Calcd. for C20H12I2O7S 0.5H2O: C,36.44; H,1.99; N,0.00. Found: C,36.50; H,2.16; N,0.09.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[O:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[O:37][C:38]([CH3:41])=[CH:39][CH:40]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)o1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)o1
Reaction time: 2 h
Yield: 81 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methylfuran-2-sulfonamide (12 mg, 0.020 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 8 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-5-methylfuran-2-sulfonamide (percentage yield: 81%), was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:12][CH2:13]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: BrCC1CCCCC1
Product: O=C(O)COCCC12CCC(c3cccc(OCC4CCCCC4)c3)(CC1)OC2
Reaction time: 0.33 h
Yield: 65 %

Procedure:
The title compound was prepared by an analogous sequence to that used to synthesize Example 51 from 7F (tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate) except that (bromomethyl)cyclohexane was used instead of (bromomethyl)cyclobutane as the alkylating agent. The crude product was purified by preparative LC/MS (Column: Waters XBridge C18, 19×200 mm, 5-nm particles; Mobile Phase A: 5:95 MeCN:water with 10-mM NH4OAc; Mobile Phase B: 95:5 MeCN:water with 10-mM NH4OAc; Gradient: 30-70% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (8 mg, 65% yield; 100% purity by LC/MS) as a light yellow oil. LCMS, [M−H]−=401. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.17 (t, J=8.1 Hz, 1H), 6.96-6.85 (m, 2H), 6.78-6.68 (m, 1H), 3.95 (s, 2H), 3.79-3.70 (m, 4H), 3.50 (t, J=6.7 Hz, 3H), 2.08-1.98 (m, 2H), 1.86-1.57 (m, 12H), 1.40 (t, J=6.7 Hz, 2H), 1.32-1.12 (m, 3H), 1.10-0.99 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)Cl>[C:43]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH2:10][CH:9]([N:8]([CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][CH3:35])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:23])=[CH:19][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15]1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.6 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (50 mg) in dry methylene chloride (1 ml) were added triethylamine (21 mg) and acetic anhydride (21 mg), and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 40 mg of 1-acetyl-5-[2-[N-tert-butoxycarbonyl- 2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an amorphous powder.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13]O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:15]=[N+:16]=[N-:17].[Na+].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C>[N:15]([CH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][F:1])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:16]=[N-:17]
Reactant: COC(=O)c1cc(CO)cc(CF)c1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CF)cc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 93 h
Yield: 52.9 %

Procedure:
Methyl 3-fluoromethyl-5-hydroxymethylbenzoate (34) (2.30 g, 11.6 mmol) was dried for 24 hours. Sodium azide (3.77 g, 58.1 mmol), carbon tetrabromide (4.24 g, 12.1 mmol), and triphenylphosphine (3.66 g, 13.9 mmol) were dried for 48 hours. Under Ar atmosphere, these were mixed with triethylamine (3.6 mL), dissolved in DMF (88 mL), and stirred for 93 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=10:1) to isolate methyl 3-azidomethyl-5-fluoromethylbenzoate (35) (1.37 g, 53%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([Cl:9])[C:6]=1[C:7]#[N:8].ClCC(O)=C(C#N)C#N.C(#N)CC#N.ClCC(Cl)=O.[NH4+]=S.NC1SC=C(O)C=1C#N.P(Cl)(Cl)(Cl)=O.[CH3:47][N:48]([CH3:51])[CH:49]=O>C(N(CC)CC)C>[Cl:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([N:1]=[CH:47][N:48]([CH3:51])[CH3:49])[S:3][C:4]=1[CH:10]=[O:11]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: CN(C)C=O
Agent: N#CC(C#N)=C(O)CCl
Agent: N#Cc1c(O)csc1N
Agent: O=C(Cl)CCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: N#CCC#N
Product: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N

Procedure:
The preparation of 2-amino-4-chloro-3-cyano-5-formylthiophene is known from EP-A-No. 193 885, according to which the intermediate triethylamine salt of 3-chloro-1,1-dicyano-2-hydroxy-1-propene is prepared from malononitrile, chloroacetyl chloride, and triethylamine and cyclized with ammonium sulfide to 2-amino-3-cyano-4-hydroxythiophene, which is then treated with a mixture of N,N-dimethylformamide and phosphoryl chloride; the N'-(4-chloro-3-cyano-5-formyl-2-thienyl)-N,N-dimethylformamidine that is formed is isolated and then hydrolyzed with formic acid, giving the required product. However, it has been found that the yield of 2-amino-4-chloro-3-cyano-5-formylthiophene obtained by this process is unsatisfactory.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=O.FC(F)(F)C([O-])=O.[O:16]=[C:17]1[NH:21][CH:20]2[CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH3+:40])=[O:30])[S:23][CH2:24][CH:19]2[NH:18]1.C1(C)C=CC=CC=1.CO.C(Cl)Cl>CC(O)=O>[Br:1][C:2]1[C:3](=[O:5])[N:40]([CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][NH:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH:20]3[NH:21][C:17](=[O:16])[NH:18][CH:19]3[CH2:24][S:23]2)[C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: [NH3+]CCOCCOCCNC(=O)CCCCC1SCC2NC(=O)NC21
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCN1C(=O)C=C(Br)C1=O
Temperature: 170 °C
Yield: 52 %

Procedure:
Monobromomaleic anhydride (45.0 mg, 0.25 mmol, 1 eq) was added in one portion to a solution of 2-(2-(2-(5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno(3,4-d)imidazol-6-yl)pentanoylamino)ethoxy)ethoxy)ethylammonium 2,2,2-trifluoroacetate (124 mg, 0.25 mmol, 1 eq) in AcOH (10 mL) and the reaction mixture heated to 170° C. for 3 h. Upon cooling to 21° C. toluene was added and the AcOH azeotropically removed in vacuo (×2) to give crude product. Column chromatography (gradient 2-10% MeOH/CH2Cl2) yielded the desired compound as a white solid (70.0 mg, 0.13 mmol, 52% yield). m.p. 95-98° C.; [α]D20.0+65.1 (c 0.15, MeOH); 1H NMR (600 MHz, CD3OD) δ 7.17 (s, 1H, CHCBr), 4.51 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 4.33 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 3.77 (t, J=5.5 Hz, 2H, OCH2), 3.68 (t, J=5.5 Hz, 2H, OCH2), 3.63 (m, 2H, OCH2), 3.58 (m, 2H, OCH2), 3.53 (t, J=5.5 Hz, 2H, NCH2), 3.37 (t, J=5.5 Hz, 2H, NCH2), 3.24 (td, J=5.0, 8.0 Hz, 1H, SCH), 2.95 (dd, J=5.0, 12.5 Hz, 1H, SCHH), 2.73 (d, J=12.5 Hz, 1H, SCHH), 2.26 (t, J=7.0 Hz, 2H, NHC(O)CH2CH2CH2), 1.69 (m, 4H, CH2CH2CH2), 1.47 (quintet, J=7.0 Hz, 2H, CH2CH2CH2); 13C NMR (150 MHz, CD3OD) δ 176.12 (s), 170.13 (s), 166.97 (s), 166.08 (s), 133.63 (s), 132.05 (d), 71.22 (t), 71.11 (t), 70.61 (t), 68.69 (t), 63.35 (d), 61.61 (d), 57.03 (d), 41.09 (t), 40.31 (t), 39.09 (t), 36.75 (t), 29.78 (t), 29.50 (t), 26.87 (t); IR (MeOH) 3355, 2970, 1737 cm−1; HRMS (ES) calcd for C20H29N4O6NaSBr [M+Na]+ 555.0889, observed 555.0905.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[CH3:12][NH:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]([N:13]([OH:14])[CH3:12])=[NH:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(O)C(=N)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a stirred solution of 2,6-difluorobenzonitrile (5.565 g, 40 mmol) and N-methylhydroxylamine hydrochloride (10 g, 120 mmol) in 4:1 water/ethanol (100 mL) was added sodium carbonate (8.5 g, 80 mmol) in small portions and the resulting mixture stirred at 100° C. for 2 h. The mixture was then cooled, concentrated and the resulting residue suspended in hot MeOH/CHCl3 (1:9, 200 mL). The insoluble solids were removed by filtration and concentration of the filtrate gave the desired product as an off-white solid (7.50 g, 100% yield). 1HNMR (500 MHz, DMSO-d6) δ: 7.69–7.63 (1H, m), 7.29 (2H, t, J=8.24 Hz), 6.90 (2H, s), 3.15 (3H, s). LCMS calcd for C8H9F2N2O (M+H): 187.07; found: 187.12.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:30]2[CH:31]=[CH:32][S:28][CH:29]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccsc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccsc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-thienylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.53 g, 43%).
Reaction SMILES: Cl.[CH2:2]([NH2:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC>[C:10]([NH:9][C:12](=[NH:13])[NH:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])#[N:11]
Reactant: CCCCCCN
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCNC(=N)NC#N

Procedure:
A mixture of hexylamine hydrochloride (63.5 g.), sodium dicyanamide (44.5 g.) and butanol (200 ml.) was heated at reflux for 18 hours and then cooled. The mixture was filtered and the filtrate was evaporated to dryness. The residue was stirred with water and the isoluble solid was collected and crystallised from aqueous ethanol, to give 3-cyano-1-hexylguanidine, m.p. 103°-105°.