Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C)C.[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:36])[C:14]([C:34]#[N:35])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7].[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:36])[C:14]([CH2:34][NH2:35])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Temperature: 100 °C
Yield: 71.7 %

Procedure:
BH3.Me2S (250 μL, 2M in THF, 0.5 mmol) was added dropwise to a solution of 6a (50 mg, 0.11 mmol) in dry THF (4 mL) at rt. The reaction vessel was sealed and heated for 60 s at 100° C. using microwave irradiation. The reaction mixture was cooled to room temperature, diluted with CH2Cl2, poured onto ice-cold aqueous HCl (1M) and agitated. The pH was then adjusted to ˜10 with 2M aqueous NaOH and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried and concentrated. The crude product was dissolved in MeOH and swirled with Amberlyst 15. The solid phase was transferred to a filtration funnel and washed with MeOH. The product was released by addition of 10% NH3 in MeOH and eluted with MeOH. Concentration of the filtrate gave 7a as a yellow solid (36 mg, 72%): [α]D−44 (c 0.25, CHCl3); IR λ 2958, 2854, 1747, 1631, 1492, 1440, 1259, 1214 cm−1; 1H NMR (400 MHz, CDCl3) δ7.83 (d, J=8.2, 1H), 7.78 (d, J=8.1, 1H), 7.71 (d, J=8.7, 1H), 7.54-7.00 (m, 9H), 5.74 (dd, J=8.6, 2.7, 1H), 4.25-4.11 (m, 2H), 3.96-3.51 (m, 8H), 3.48 (dd, J=11.8, 2.7, 1H); 13C NMR (100 MHz, CDCl3) δ168.1, 161.3, 153.5, 148.9, 135.8, 133.8, 133.6, 131.2, 129.7, 129.3, 128.7 (splitted), 128.5 (splitted), 127.3, 126.3, 125.9, 125.5, 124.4, 123.2, 118.4, 116.6, 64.2, 53.6, 38.0, 33.2, 31.7; HRMS (FAB+) calcd for C27H24N2NaO3S 479.1405, obsd 479.1405.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:24]([O:28][C:29](=[O:41])[NH:30][C@@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:41])[NH:30][C@@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH:38][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][N:12]4[CH:13]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[N:10]=[N:11]4)[CH:16]=3)[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2nc(N)sc2C1
Reactant: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)O)c3)nn2)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1

Procedure:
React 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid and ((R)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester under TBTU coupling conditions as described in Example 1 to give ((R)-2-{3-[4-(4-cyano-phenyl)-1,2,3-triazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([O:15][CH2:16]Cl)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:13][CH3:14]
Reactant: CCCOCCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOCOc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
To a solution of methyl salicylate (0.637 g, 4.19 mmol) in N,N-dimethylformamide (8 ml) were added chloromethyl propyl ether (0.50 ml, 4.54 mmol) and potassium carbonate (0.755 g, 5.46 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-propoxymethoxybenzoate (0.414 g, 1.85 mmol, yield 44%). This was dissolved in methanol (5 ml), 1N-aqueous sodium hydroxide solution (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-propoxymethoxybenzoic acid (0.374 g, 1.78 mmol, yield 96%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]1.O>CN1C(=O)N(C)CCC1>[OH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11]1
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1cccc(F)c1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: N#Cc1cccc(N2CC[C@@H](O)C2)c1
Temperature: 180 °C
Yield: 62.7 %

Procedure:
3-Fluorobenzonitrile (0.385 g, 3.18 mmol) and (3R)-pyrrolidin-3-ol (0.278 g, 3.19 mmol) were dissolved in DMPU (3 mL). The resulting mixture was subjected to microwave heating at 180° C. for 5 h. Water was added and the mixture extracted with ether. The organic layer washed with water, dried with MgSO4, filtered and concentrated. Purification on a 10 g Isolute Flash Si column (heptane/EtOAc 2:1→1:1) gave 0.375 g (63%) of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.22 (dd, 1H, J=8.5, 7.5 Hz), 6.82 (d, 1H, J=7.5 Hz), 6.72 (dd, 1H, J=8.5, 2.2 Hz), 6.69 (bs, 1H), 4.48 (m, 1H), 3.42-3.33 (m, 2H), 3.24 (ddd, 1H, J=8.8, 8.8, 3.4 Hz), 3.13 (bd, 1H, J=10.5 Hz), 2.14-1.94 (m, 2H). 13C NMR (MeOH-d4) δ 149.2, 130.9, 120.6, 119.5, 117.0, 114.9, 113.4, 71.4, 56.7, 46.5, 34.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][N:32]1[CH:36]=[C:35]([S:37]([Cl:40])(=[O:39])=[O:38])[N:34]=[CH:33]1>ClCCl>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][N:22]([CH3:23])[S:37]([C:35]4[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=4)(=[O:39])=[O:38])[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CNCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)S(=O)(=O)c1cn(C)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.9 %

Procedure:
Dissolve {2-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.032 g, 0.101 mmol) in dichloromethane (5 mL). Add triethylamine (16 μL, 0.209 mmol) followed by 1-methyl-1H-imidazole-4-sulfonyl chloride (0.020 g, 0.112 mmol) and stir at ambient temperature for 72 hr. Concentrate under reduced pressure and purify (silica gel chromatography, eluting with 20:80 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate, then 20:80 methanol:ethyl acetate) to give the free base of the title compound (23 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>N1C=CC=CC=1>[CH2:30]([S:32]([NH:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:34])=[O:33])[CH3:31]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3c(N)cccc3NC(=O)C2)cc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc2c1N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(=O)N2
Reaction time: 1 h

Procedure:
A suspension of the aniline from example 14 (0.5 g, 1.3 mmol) in dry pyridine (3 ml) was treated with ethanesulphonyl chloride (0.133 ml, 1.4 mmol). After 1 h, the mixture was evaporated to dryness then partitioned between dichloromethane and dilute aqueous sodium bicarbonate. The organic phase was dried over magnesium sulphate and evaporated to a yellow solid which was recrystallised from ethyl acetate (0.37 g, 59%). M.p. 258°-260° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH2:9][N:10]=[N+:11]=[N-:12])=[O:5])C.[OH-]>CO.O>[N:10]([CH2:9][C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3])=[N+:11]=[N-:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CN=[N+]=[N-]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of trans-ethyl-2-azidomethyl-1-cyclopropane carboxylate (7.282 g, 37.13 mmol) in a mixture of methanol (20 ml) and water (10 ml) was cooled to 0° C. and treated dropwise with 40.8 ml of 1 M solution hydroxide in water (40.8 mmol). After the addition was completed the bath was removed and the solution was stirred at room temperature for 3 h. The methanol was evaporated under reduced pressure and the aqueous solution was extracted with ether (2×10 ml). After acidification with dilute hydrochloric acid (3 N), the aqueous phase was extracted with dichloromethane (4×25 ml) and the combined organic extracts washed with water (10 ml), brine (10 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation (bulb to bulb) of the residue under vacuum gave 4.830 g (92%) of a clear oil; bp 100°-108° C./0.6 mm Hg (air bath temperature); ir (film) νmax : 2095 (N3), 1695 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.25 (2H, d, J=6, CH2N3), 2.0~0.6 (4H, m, cyclopropyl), 12.3 (1H, s, COOH). Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.77; Found: C 42.55, H 4.89, N 29.75.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]2=[O:29])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.[O:39]=[C:40]1[CH2:45][O:44][C:43]2[CH:46]=[CH:47][C:48]([CH:50]=O)=[N:49][C:42]=2[NH:41]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[CH2:20][O:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:50][C:48]4[CH:47]=[CH:46][C:43]5[O:44][CH2:45][C:40](=[O:39])[NH:41][C:42]=5[N:49]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)OC2

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-1,4-dihydro-2H-3,1-benzoxazin-2-one trifluoro acetate (Intermediate 106) (324 mg, 0.78 mmol) was converted to the free base using N,N-diisopropylethylamine for 30 minutes and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (153 mg, 0.86 mmol) and sodium cyanoborohydride (98 mg, 1.56 mmol) as described under Example 21. The reaction mixture was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (9:1) gave the free base of the title compound as a colorless foam. The free base was taken up in 1,4 dioxane (2 mL), followed by addition of 4M HCl in 1,4-dioxane (0.30 mL). The resulting precipitate was collected by filtration and gave 75 mg (48%) of the bis-hydrochloride salt of the product.
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[NH2:15][OH:16].C(N(CC)CC)C>C(O)C.O>[F:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10](=[N:15][OH:16])[NH2:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: NO
Reactant: N#Cc1ccc(C2(F)COC2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(C2(F)COC2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 4-(3-fluorooxetan-3-yl)benzonitrile (Step 2, 450 mg, 2.54 mmol), hydroxylamine hydrochloride (388 mg, 5.59 mmol) and triethylamine (779 μL, 5.59 mmol) in ethanol (12.5 mL) was stirred and heated at reflux over night. After being cooled to rt, the reaction mixture was diluted with water (75 mL) whereupon the product precipitated. Filtration, washing with water and drying in a vacuum oven afforded a first crop of the title compound (360 mg, 67%). A second crop was obtained after concentration of the filtrate (122 mg, 21%, purity 90%): 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.77 (d, 2H), 7.54 (d, 2H), 5.87 (broad s, 2H), 4.97 (dd, 2H), 4.91 (dd, 2H); DCI(NH3)-MS m/z 211 (MH)+; HPLC RT (Method I) 2.64 min.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:12]([CH3:13])=[CH:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].CC1[C:20](=[O:21])[CH2:19][CH:18](C(C)=C)CC=1.ClCCC(OCC)=O.C(C(CC)=O)=C>>[C:4]([C:6]12[CH2:18][CH2:19][C:20]([OH:21])=[CH:13][C:12]1=[CH:11][C:9](=[O:10])[CH2:8][CH2:7]2)([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: C=CC(=O)CC
Agent: CCOC(=O)CCCl
Product: CCOC(=O)C12CCC(=O)C=C1C=C(O)CC2

Procedure:
This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:27][CH:26]=2)[C:19]([CH3:41])=[C:18]3[CH3:42])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([NH:38][S:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C@H:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)[CH3:11])=[O:14])=[CH:23][CH:22]=3)[C:18]([CH3:42])=[C:19]2[CH3:41])=[CH:26][CH:27]=1)(=[O:39])=[O:40])(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of (S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-sulfamoyl-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide (0.058 g, 0.1 mmol) and TEA (0.03 mL, 0.2 mmol) in DCM (0.5 mL) was slowly added acetyl chloride (0.009 g, 0.11 mmol). The mixture was stirred at room temperature for 1 h.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Br[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].[H-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[C:7]([S:9]([N:12]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:28][CH2:29][N:30]2[C:34](=[O:35])[CH2:33][CH2:32][C:31]2=[O:36])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CN(C)CCNS(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Reactant: O=C1CCC(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(CCN1C(=O)CCC1=O)S(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide (41.4 mg, 0.1 mmol) in dry DMF (2 ml) was added 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione (30.9 mg, 0.15 mmol) and NaH (60%, 6.00 mg, 0.15 mmol). The mixture was stirred for 8 hours at 90° C. After cooled to room temperature, the solvent was evaporated. The mixture was diluted with EtOAc (60 ml), washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by preparative TLC (CH2Cl2/CH3OH=20/1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-N-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-benzenesulfonamide (44 mg, 81.6%) and the free base was converted into HCl salt by 4N HCl in dioxane.
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]([C:32]([NH:34][CH2:35][CH:36](OC)[O:37]C)=[O:33])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[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]([C:32]([NH:34][CH2:35][CH:36]=[O:37])=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NCC(OC)OC)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(-c2csc3c(C(=O)NCC=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 70.3 %

Procedure:
4-Amino-N-(2,2-dimethoxyethyl)-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.18 mmol), trifluoroacetic acid (2 mL), and water (4 mL) were combined at ambient temperature for 2 hours. Mixture was diluted with a solution of saturated sodium bicarbonate (50 mL) and filtered to yield the title compound (65 mg, 70% yield): 1H NMR (DMSO, 400 MHz) δ 9.59 (s, 1H), 9.50 (s, 1H), 9.13 (m, 1H), 8.61 (s, 2H), 8.08 (d, 1H), 7.79 (s, 1H), 7.65 (dd, 2H), 7.32–7.35 (m, 2H), 7.25 (s, 1H), 7.10–7.16 (m, 2H), 4.16 (d, 2H), 4.04 (s, 3H), 3.92 (s, 3H); RP-HPLC (5% to 95% acetonitrile over 5 minutes, 1 ml/min, 254 nm, betasil HS 100 Å, C18, 5 μm, 50×2.1 column) Rt 3.54 min. MS: 531.0 MH+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].N([O-])=O.[Na+].[BrH:15]>O>[Br:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(N)cc1C#N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Water (13.5 mL), HBr (74%, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chomatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4]1.[CH3:18]N(C)C=O>C1(C)C=CC=CC=1>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:6][CH2:5][O:3][CH2:4][CH3:18]
Reactant: CCCCCCCCCCCCC1CO1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCO
Product: CCOCC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
15.0 g (0.035 mol) of the polyerythritol prepared in Example 1 and 0.15 g of sodium hydroxide were dissolved in 20 ml of N,N-dimethylformamide while heating at 150° C. in a dried nitrogen gas flow, and stirred for 30 minutes. 14.8 g (0.070 mol) of 1,2-epoxytetradecane in 50 ml of N,N-dimethylformamide was added to the mixture, which was further stirred for four hours at 105° C. in a dried nitrogen gas flow. After the reaction, N,N-dimetylformamide was evaporated to obtain adcrude product. After dissolving the crude product in 100 ml of hot toluene and cooling the solution to room temperature, unreacted polyerythritol was filtered out. The toluene in the filtrate was evaporated in vaccuo to obtain 28.5 g of a white powdery desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].[CH3:10]OC(OC)OC>>[CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](/[O:6][CH3:10])\[CH2:7][Cl:8]
Reactant: COC(OC)OC
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)/C=C(\CCl)OC
Temperature: 150 °C
Yield: 75 %

Procedure:
31.0 g (0.2 mol) of 4-chloro aceto acetic acid methyl ester was mixed with 106.0 g (1.0 mol) of orthoformic acid trimethyl ester. 30.0 g of Amberlyst-15 ion exchange resin was added under argon with stirring. The reaction temperature rose to 40° C. with vigorous development of gas. After 5 hours of stirring, no educt could any longer be detected by thin-layer chromatography. The ion exchange resin was filtered off, and the residue was distilled in a water jet vacuum. The distillate was mixed with 1.0 g of p-toluenesulfonic acid monohydrate and slowly heated to 150° C., whereby methanol distilled off. The reaction mass was then distilled in a water jet vacuum. 24.7 g of a colorless liquid with a boiling point bp12 =93° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1ccc(F)c(-c2cncc(Br)c2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cc(F)ccc5F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2,5-difluoro-phenyl)-pyridine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:14][CH:13]=1.C[C:22](C)=[O:23].[OH:25]S(O)(=O)=O.O=[Cr](=O)=O>>[C:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:14][CH:13]=1)([OH:23])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=O
Reactant: C[Si](C)(C)c1cc(CCCCCCCCCCO)co1
Agent: O=[Cr](=O)=O
Product: C[Si](C)(C)c1cc(CCCCCCCCCCC(=O)O)co1

Procedure:
3-(10-Hydroxydecyl)-5-trimethylsilylfuran is oxidized by Jones reagent (chromic acid) to give 3-(10-carboxydecyl)-5-trimethylsilylfuran. A mixture of this compound and Rose Bengal in tetrahydrofuran is exposed to singlet oxygen at -78° to give 4-(10-carboxydecyl)-5-hydroxy-2(5H)-furanone.