Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@:17]([CH3:23])([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)[C@](C)(N)CO
Product: CC(C)[C@@](C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 7533-40-6) as starting materials and isolated (21 mg, 73%) as colorless oil; MS (ESI, m/z): 327.2 (MH+).
Reaction SMILES: [H-].[Na+].CN([C:6]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:8]=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].P([O-])(O)(O)=O.[Na+]>CN(C)C=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:8][C:7]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: CSc1ccc(C(C=O)=C(c2ccc(F)cc2)N(C)C)cc1
Reactant: N#CCC(N)=O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 1.45 g of 60% dispersion of sodium hydride in mineral oil (containing 869 mg, 36.2 mMol), washed once with hexane, in 20 ml of dry dimethylformamide, was added dropwise a solution of 9.42 g (29.9 mMol) of 1-(N,N-dimethylamino)-1-(4-fluorophenyl)-2-(4-methylthiophenyl)prop-1-en-3-one from Step 4, cyanoacetamide (2.59 g, 30.3 mMol), and 2.9 ml of methanol in 50 ml of dimethylformamide. After the addition was complete, the resulting dark solution was stirred overnight at 70-80° C. After cooling, the mixture was added in portions to 500 ml of 1M aqueous sodium dihydrogen phosphate, producing a yellow solid. The solid was filtered, washed with water, and dried to give 9.24 g of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]=O>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Solvent: O=CO
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN(C)CCO1
Temperature: 95 °C
Yield: 91 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine (3.32 g, 7.7 mmol) in formic acid (33.2 mL) was added a 37 wt % solution of formaldehyde in water (3.32 mL), and the reaction mixture was heated at 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in methanol and treated with Bio-Rad AG®1-X8 hydroxide form resin until pH 8. Filtration and concentration in vacuo afforded 3.11 g (91%) of the title compound as a yellow-brown solid. 1H NMR (400 MHz, d4-MeOH): 8.46 (s, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 4.21-4.09 (m, 2H), 4.02 (s, 3H), 4.01-3.91 (m, 3H), 2.96 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.22 (m, 1H), 2.11 (t, 1H); MS (EI) for C21H22N4O3Cl2: 449 (MH+).
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1Cl)=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:13])[CH3:10].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:33])[CH2:27][CH2:28]1)=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)c2cnccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Temperature: 110 °C
Yield: 92.1 %

Procedure:
DABCO (0.7 g, 6.3 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester (120) (0.8 g, 3.16 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (0.93 g, 4.74 mmol) DMA at room temperature. The solution was heated at 110° C. for 2 h. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield 1.2 g (92%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) as white solids. MP: 231° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.18 (m, 4H), 3.89 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 7.14 (dd, J=3.6, 4.8 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.91 (s, 1H); EIMS m/z 413 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:23]1(=O)[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12

Procedure:
The material prepared in Example 1A (250 g, 1.19 mole) was combined with zinc chloride (243.5 g, 1.784 mole) and toluene (3.75 L). The reaction mixture was heated to reflux under a nitrogen atmosphere. Benzoquinone (167 g, 1.546 mole) in tetrahydrofuran (500 mL) was added dropwise to the reaction, and upon completion of the addition, the reaction mixture was heated at reflux for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to a brown solid. The solid was recrystallized from acetonitrile yielding the title compound as a brown solid (125 g, 35%). MS m/z 301 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]1>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCNC1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC(CO)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 114 g. of 3-piperidinemethanol in 900 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate for 1-(4-acetylbenzenesulfonyl)-3-piperidinemethanol collected by filtration, washed with water and dried; m.p. 104°-106° C. after crystallization from aqueous ethanol.
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[C:29]([NH2:32])(=[NH:31])[CH3:30].CCN(C(C)C)C(C)C.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[CH:25]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][N:32]=[C:29]([CH3:30])[N:31]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:26][CH2:27]1
Reactant: CC(=N)N
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)ns3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 0.042 g, 0.111 mmol), acetamidine hydrochloride (10.49 mg, 0.111 mmol), and Hünig's Base (0.058 mL, 0.333 mmol) in DMF (0.617 mL) was stirred at rt ON. Diethyl azodicarboxylate (0.088 mL, 0.222 mmol) was added and stirring continued at room temperature for 16 h. The reaction mixture was concentrated. The residue was taken up in MeOH and purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (4.32 mg, 9% yield) was isolated as a pale yellow solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[I-].[Na+].[CH2:46]([NH2:48])[CH3:47]>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][CH:18]4[CH2:24][CH2:25][N:48]([CH2:46][CH3:47])[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnc(C)cn3)c2)C1=O
Yield: 116.2 %

Procedure:
Ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (27 mg, 0.04 mmol), sodium iodide (7 mg, 0.04 mmol) and ethylamine (2M in THF; 45 μL, 0.09 mmol) in acetonitrile (2 mL) were heated in a microwave at 120° C. for 90 minutes. Solvent evaporated under reduced pressure and the residue diluted with ethyl acetate (20 mL) and brine (20 mL). The organics were separated and the aqueous layer re-extracted with ethyl acetate (20 mL). The combined organics were dried (MgSO4) and concentrated and the residue purified by preparative HPLC, eluting with a gradient of 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid on a Phenomenex Luna 10u C18(2) 100A column, to afford product (24 mg, 87%). 1H NMR δ (300 MHz, CDCl3) 1.19 (3H, t), 2.17-2.26 (1H, m), 2.34-2.44 (2H, m), 2.62-2.74 (4H, m), 3.39-3.59 (4H, m), 4.30 (2H, s), 4.76 (2H, s), 5.11 (1H, t), 6.95 (1H, t), 7.29 (1H, t), 7.39-7.42 (1H, m), 7.52 (1H, d), 8.10 (1H, d), 8.19 (1H, s), 8.36 (1H, d), 9.65 (1H, d); m/z 517 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][Zn+])#[N:3].Cl[C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[CH:12][CH:11]=1.CCOC(C)=O.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=2)=[CH:12][CH:11]=1)#[N:3]
Reactant: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1ccc(Cl)nn1
Reactant: N#CCCCC[Zn+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCCCCc1ccc(NC(=O)Cc2cccc(OC(F)(F)F)c2)nn1
Reaction time: 4 h

Procedure:
4-Cyanobutylzinc bromide solution (3.0 equiv., 0.50 mol, 1.0 L) was charged into an argon gas purged 5000 mL 3 neck round bottom flask. Argon(g) purge for 5 minutes followed by the addition of 1117 (1.0 equiv., 0.167 mol, 55.3 g) and NiCl2(dppp) (0.15 equiv., 0.0251 mol, 13.6 g) under a blanket of argon(g). The reaction usually goes to completion after 4 hours (TLC: 1:1 hexanes-ethyl acetate). EtOAc (15 vol., 832 mL) added to deep red solution. Water (15 vol., 832 mL) was added, thick slurry formed. 1N HCl added until slurry breaks to pale blue layer (˜6 vol., 333 mL). Transferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL), dried (MgSO4) and concentrated by rotary evaporation (bath≦30° C.) to a solid reddish oil. Oil dissolved in dichloromethane (15 vol., 832 mL), silica gel (100 g) was slurried into red solution, this was concentrated by rotary evaporation (bath≦30° C.) to a solid reddish powder. Loaded onto a bed of silica gel (5 cm×11 cm), flushed with 25% hexanes in ethyl acetate (3 L), combined organics concentrated by rotary evaporation (bath≦30° C.). Dried under high vacuum to a constant weight to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1118: yield of 58.2 g (92%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.52-7.27 (m, 4H), 3.89 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 90.1 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.3 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 89% based on benzenesulfonyl cyanide).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[N:20]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(Quinolin-2-ylmethoxy)-phenylamine (1.73 g) in 30 mL of concentrated HCl at 0° C. was added sodium nitrite (531 mg). After 3 h, tin chloride (3.95 g) was dissolved in 20 mL of concentrated HCl and added slowly dropwise and the reaction mixture stirred at ambient temperature for 18 h. The reaction mixture was filtered and the solid dried to provide the title compound as the HCL salt (3.94 g). MS: (M+H m/z=266.3).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:14][C:13]=2[CH:30]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:14][C:13]=2[CH:30]=1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1S(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCOC(=O)c1sc2cc(O)ccc2c1S(=O)c1ccccc1
Yield: 78.6 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a stirred mixture of ethyl 6-(benzyloxy)-3-(phenylsulfinyl)benzo[b]thiophene-2-carboxylate (Example 31, 4.9 g, 11.2 mmol) and methyl phenyl sulfide (5.2 ml, 45 mmol) at ambient temperature under a nitrogen atmosphere. After 20 hours the solvents were removed under reduced pressure, and the residue was azeotroped using toluene. The residue was flash chromatographed on silica gel using 2% ethanol in dichloromethane as eluant. The isolated product was crystallised from diisopropyl ether to give the title compound as a colourless solid (3.05 g).
Reaction SMILES: [CH2:1]([N:5]1[CH:9](P(=O)(OCC)OCC)[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[Cl-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39]([CH:42]=O)=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]>C(#N)C>[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39](/[CH:42]=[C:9]2\[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:19])[NH:7][C:8]\2=[O:18])=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1Cl
Reactant: CCCCN1C(=O)NC(=O)C1P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCc1ncc(/C=C2/C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (0.49 g, 1.72 mmol) in acetonitrile (5 mL) was added lithium chloride (0.15 g, 3.47 mmol) and then DBU (0.52 mL, 3.47 mmol). This mixture was stirred for 5 minutes under N2. Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-3-chlorobenzoate (0.48 g, 1.43 mmol) in acetonitrile (5 mL) was added and the mixture stirred for 4 days. The solvent was removed in vacuo and the isomers separated by chromatography eluting with (1-5)% methanol in chloroform.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+].Cl>O.O1CCCC1>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C(C)C)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C(=O)O)c2)CC1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of methyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate (1.25 g, 3.9 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-isobutyrylpiperazine-1-carbonyl)benzoic acid (1.1 g, yield 76%). LC-MS (ESI) m/z: 305 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH:67](=O)[CH2:68][CH2:69][CH2:70][CH3:71].C([BH3-])#N.[Na+]>CO>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: CCCCC=O
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNC[C@H]1OC(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Yield: 13 %

Procedure:
The title compound is prepared by the procedure of Example 17, using 50.0 mg (53 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 0.4 ml of methanol, 4.7 mg (1.0 eq., 55 μmol) of valeraldehyde and 3.3 mg (1.0 eq., 53 μmol) of sodium cyanoborohydride to give 7.0 mg of the desired product.
Reaction SMILES: C([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:7]([C:18]#[N:19])[CH2:6]1)(C)(C)C.ClC(OC(Cl)C)=O.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.CO>ClCCCl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C@@H:8]1[CH2:9][NH:5][CH2:6][CH:7]1[C:18]#[N:19]
Reactant: CC(C)(C)N1CC(C#N)[C@H](c2ccc(F)cc2F)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CO
Solvent: ClCCCl
Product: N#CC1CNC[C@H]1c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-1-t-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carbonitrile (4 g, 15.15 mmol) prepared according to the procedure described in WO 2004/09126 in DCE (10 ml) was added dropwise 1-chloroethyl chloroformate (2.45 ml, 22.68 mmol) at 0° C. The reaction solution was heated to 70° C., and maintaining this temperature, 1.8-bis(dimethylamino)naphthalene (4.87 g, 22.72 mmol) in DCE (10 ml) was added dropwise for 2 h. After the reaction finished, methanol (10 ml) was added, and maintaining the temperature, the reaction mixture was stirred for additional 1 h, concentrated in vacuo, and the next reaction was carried out without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:13][C:14]1[CH:18]=[C:17]([NH:19][S:20]([C:23]2[S:24][C:25](Br)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[O:16][N:15]=1>>[CH3:13][C:14]1[CH:18]=[C:17]([NH:19][S:20]([C:23]2[S:24][C:25]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[O:16][N:15]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)on1
Yield: 20.9 %

Procedure:
N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 3-nitrobenzene boronic acid (362 mg, 2.17 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (700 mg, 2.17 mmol). Purification by column chromatography using 10% MeOH/CHCl3 gave 166 mg of the pure sulfonamide (21% yield).