Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([OH:28])CO)=[O:12].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:28])=[O:12]
Reactant: O=C(CCCCCCCCC(O)CO)OCOC(=O)CCCCCCCCC(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCCCCCCC(=O)OCOC(=O)CCCCCCCCC=O

Procedure:
Methylene bis(10,11-dihydroxyundecanoate) (2.24 g, 5 mmol) was dissolved in 150 ml tetrahydrofuran. Sodium metaperiodate (2.06 g, 10 mmol) was dissolved in 150 ml water and added dropwise to the tetrahydrofuran solution. TLC indicated full consumption of the diol after 60 minutes, whereupon sodium chloride was added to the reaction mixture until the two phases separated. The water phase was extracted with diethyl ether (3×50 ml). The combined organic phases was dried with magnesium sulphate and evaporated to give the title product as an oil, 1.43 g (74%). 13C NMR (45 MHz) CDCl3 : δ 21.9-43.9 (16×CH2), 79.1 (O--CH2 --O), 173.0 (2×C=O), 202.6 (2×CHO).
Reaction SMILES: C1(C=O)CC1.C[C@H]([C@@:10]1([OH:20])[CH2:15][C@@H:14](C)[CH2:13][CH2:12][C@@H:11]1[CH:17]([CH3:19])C)C=C.CC1C[C@H](O)[C@@H](C(C)C)CC1>>[CH:11]1([C@H:10]([OH:20])[CH2:15]/[CH:14]=[CH:13]/[CH3:12])[CH2:17][CH2:19]1
Reactant: C=C[C@H](C)[C@@]1(O)C[C@@H](C)CC[C@@H]1C(C)C
Agent: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: O=CC1CC1
Product: C/C=C/C[C@@H](O)C1CC1

Procedure:
Using the method described by J. Nokami et al., J. Am. Chem. Soc. 2001, 123, 9168-9169, cyclopropanecarbaldehyde was reacted with (1S,2R,5S)-1-[(2S)-but-3-en-2-yl]-5-methyl-2-(propan-2-yl)cyclohexanol [this crotylation reagent was derived from (+)-menthol] to afford the product as an oil. Yield: 600 mg, 4.75 mmol, 100%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 5.45-5.63 (m, 2H), 2.86-2.92 (m, 1H), 2.33-2.41 (m, 1H), 2.20-2.29 (m, 1H), 1.69-1.72 (m, 3H), 0.47-0.56 (m, 2H), 0.27-0.37 (m, 1H), 0.16-0.26 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29].N1C=CC=CC=1>C(OCC)C>[C:28](=[O:29])([O:30][CH2:31][CH2:32][O:33][CH3:34])[O:24][C:22]1[CH:23]=[C:18]([N:5]2[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:19]([F:26])=[CH:20][C:21]=1[Cl:25]
Reactant: COCCOC(=O)Cl
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(=O)OCCOC)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone and 2-methoxyethyl chloroformate with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-2-chloro-4-fluorophenyl} 2-methoxyethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.39 ppm (d,1H), 7.26 ppm (d,1H), 6.64 ppm (s,1H), 4.39°-4.56 ppm (m,4H), 3.70 ppm (m,2H), 3.43 ppm (s,3H), 1.30 ppm (t,3H):
Reaction SMILES: C1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3]C1.C1C2N(CC=C(C3C4C(=CN=CC=4)NC=3)C2)CC1>C(O)C.[Pd]>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:17](=[CH:16][CH:15]=[N:14][CH:13]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: c1cnc2[nH]cc(C3CCN4CCCC4C3)c2c1
Agent: [Pd]
Agent: C1=C(c2c[nH]c3cnccc23)CC2CCCN2C1
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccncc23)CC1

Procedure:
3-(Octahydro-7-indolizinyl)-1H-7-azaindole (less polar isomer 134.2 mg, 49.5% and more polar isomer 36.6 mg, 13.3%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-6-azaindole (270 mg, 1.13 mmol) and 10% Pd/C (300 mg) in ethanol (4 mL) under H2 overnight.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][C:5](C(OCC)=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][O:3]1.[Cl-].[Na+].O.C(O)C>CS(C)=O>[CH3:1][C:2]1([CH3:18])[O:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:7]1
Reactant: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1COC(C)(C)OC1
Temperature: 180 °C
Yield: 53.2 %

Procedure:
To a solution of the product of Example 2 (65 g) in dimethyl sulfoxide (65 g) is added sodium chloride (1 g). The mixture is stirred while warming at about 180° C., and water is added in small portions while maintaining the temperature between 170° and 180°. Ethanol and water are evolved and are removed by distillation until about 60 ml of liquid has been collected. The mixture is cooled, ether (200 ml) added, and the mixture partitioned with 3 portions of water (50 ml). The organic phase is dried over sodium sulfate and evaporated to a residue. Distillation of the residue gives the title product (25 g) (57%) B.P. 38° (0.01 mm) nD26 1.4400.
Reaction SMILES: N1C2C(=CC=CC=2)CC1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[O:29])=[CH:27][C:21]=3[N:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH:32]1S(C1C=CC(C=O)=CC=1)(=O)=O.C(NS(C1C=CC(C=O)=CC=1)(=O)=O)C1C=CC=CC=1>>[N:31]1([S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[O:29])=[CH:27][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: O=Cc1ccc(S(=O)(=O)C2Cc3ccccc3N2)cc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(S(=O)(=O)C4Cc5ccccc5N4)cc3)nc2c1
Agent: O=Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(S(=O)(=O)N4CCc5ccccc54)cc3)nc2c1

Procedure:
2-[4-(2,3-Dihydro-indole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. This compound was prepared as described in Example 46 substituting 4-(2,3-dihydro-indole-2-sulfonyl)-benzaldehyde (202 mg, 0.703 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. The title compound was obtained as a beige powder, 130 mg (44%). HPLC (Method C): Rt=4.80. MS (ESI): mass calculated for C22H18N4O3S, 418.5; m/z found, 419.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (d, J=8.2 Hz, 2H), 8.22 (s, 1H), 8.04 (m, 3H), 7.84 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.20 (m, 2H), 7.01 (m, 1H), 4.01 (t, J=8.2 Hz, 2H), 2.94 (t, J=8.1 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=2)[CH:31]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:29]=[N:28][CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:33]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cncc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cncc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 5-phenylnicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 403.36 g/mol.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C=O>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
(1-Carboxymethyl-3-hydroxy-2-methyl-pyrid-4-one)3 -AL+3 (4.5 g) in 200 ml of dimethylformamide (DMF) has added N-hydroxysuccinimide (2.9 g! followed by addition of dicyclohexylcarbodiimide (5.2 g) dissolved in 100 ml of DMF, is stirred and left to stand over night. The reaction produces a white precipitate, N,N'-dicyclohexylurea that is filtered off and discarded. Glucosamine [5.4 g] is added to the filtrate and allowed to react for 2 h, and then the pH is adjusted to 2.5 with sulphuric acid and rotary evaporated to dryness and is then extracted with several volumes of hot methanol. The combined extracts are concentrated until precipitation begins after which the solution is stored in refrigerator over night to complete precipitation of 2-deoxy-2-(N-carbamoylmethyl-[N'-2'-methyl-3'-hydroxypyrid-4'-one])-D-glucopyranose. Molecular mass, M+=382.8, by mass spectroscopy. The compound dissolved in ethanol/water mixture with added iron forms the purple coloured complex. HPLC analysis of mixture of 3-hydroxy-2-methyl-4-pyrone control and synthetic end product which showed a single sharp peaks well separated from the control.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([CH:9]=1)[NH2:8].[Sn](Cl)Cl>CCO>[CH3:1][S:2][C:3]1[CH:9]=[C:7]([NH2:8])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: CSc1ccc([N+](=O)[O-])c(N)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CSc1ccc(N)c(N)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
5-(Methylthio)-2-nitroaniline (12.9 g, 70.1 mmol) was dissolved In 475 mL of EtOH with stirring. Tin (II) Chloride (74.0 g, 392 mmol) was added and the reaction was refluxed for 20 h. The reaction was cooled to rt and concentrated in vacuo to a volume of 150 mL. The pH of the solution was adjusted to approximately 10 using concentrated aqueous 3N NaOH. EtOAc (1.5 L) was added and the reaction was filtered through Celite, washing with water and EtOAc. The aqueous layer was separated, then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 10.7 g (99%) of the crude 4-(methylthio)benzene-1,2-diamine as a dark oil. 1H NMR (400 MHz, DMSO-d6) δ 6.52 (m, 1H), 6.44 (m, 1H), 6.37 (m, 1H), 4.49 (br s, 4H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1.CN([CH:18]=[O:19])C.C(N1C=CN=C1)(N1C=CN=C1)=O>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:14][C:18](=[O:19])[N:8]2[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1N
Reactant: CN(C)C=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
To a microwave vial is added the crude (2-chloro-5-amino-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 2.3 mmol) and anhydrous DMF (15 mL) followed by 1,1′-carbonyldiimidazole (1.1 g, 7.0 mmol). Sealed vial and microwave are heated at 100° C. for 10 min. The reaction mixture is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/Hexane 1:1) gives 0.3 g of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one. LCMS: 241.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([I:56])=[CH:52][CH:51]=1)[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]([C:50]1[CH:51]=[CH:52][C:53]([I:56])=[CH:54][CH:55]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Reactant: CCCCNc1ccc(I)cc1
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(I)cc1
Yield: 4.4 %

Procedure:
Following a procedure analogous to that for the synthesis Intermediate 122G, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 116 mg, 0.18 mmol) and N-butyl-4-iodoaniline (Okano, K. et al., Org. Lett., 5:4987-4990 (2003)) (59 mg, 0.22 mmol) were converted to the title compound (7 mg, 41%). 1H NMR (MeOD, 1:1 mixture of amide rotamers) δ 8.65 (s, 1H), 8.15-8.07 (m, 1.5H), 8.05-8.00 (m, 3.5H), 7.95 (d, J=8.0 Hz, 1H), 7.69-7.54 (m, 3H), 7.45-7.31 (m, 2H), 7.20-7.17 (m, 4H), 7.03-7.00 (m, 0.5H), 6.97-6.96 (m, 0.5H), 6.70 (d, J=8.6 Hz, 1H), 6.43 (br s, 1H), 4.93 (br s, 0.5H), 4.68 (br s, 0.5H), 4.48 (br s, 0.5H), 4.35 (br s, 0.5H), 3.83 (br s, 1H), 3.71 (br s, 1H), 3.61-3.45 (m, 2H), 3.11-3.01 (m, 1H), 2.92-2.78 (m, 1H), 2.16 (s, 3H), 1.41-1.22 (m, 4H), 0.91-0.80 (m, 3H); MS(ESI+) m/z 886.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10]2)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 80.3 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(2-chloro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 255) (0.80 g, 2.2 mmol), SnCl2 (1.7 g, 8.8 mmol), 6N HCl (2 drops) and EtOH (15 ml) gave the title compound (0.59 g, 80%) which was used in the next steps without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH:28]=[N:27][C:26]([NH2:29])=[N:25]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:29][C:26]3[N:27]=[CH:28][N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:31])([F:16])[F:30])[N:25]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(-c2ccccc2C(F)(F)F)n1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4C(F)(F)F)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2-trifluoromethyl-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a brownish solid (Yield=77%). MS ISP (m/e): 410.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:25]([CH2:27][C:28]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)=[O:29])#[N:26]
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)CC#N)c2)cn1
Yield: 69.9 %

Procedure:
A mixture of Example C1 (0.15 g, 0.455 mmol), cyanoacetic acid (0.080 mL, 1.206 mmol), TBTU (0.258 g, 0.804 mmol) and DIEA (0.35 mL, 2.009 mmol) in DMF (5 mL) was stirred at RT overnight, treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via preparative TLC (MeOH/DCM/TEA) to afford N-((5-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (126 mg, 79%). 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.92 (s, 1H), 10.44 (s, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.22 (d, J=5.8 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.56 (s, 1H), 6.76 (dd, J=5.7, 2.4 Hz, 1H), 3.93 (s, 2H), 1.21 (s, 9H); MS (ESI) m/z: 397.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:31])[C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[C@H:10]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:31])[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C@H:10]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](=[O:49])[C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OCc3ccccc3)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(O)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
80 mg (3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepane-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran. 10 mg 5% palladium on charcoal was added and the mixture hydrogenated at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered on, the pad washed with tetrahydrofuran and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on silica gel (10 g, AcOEt/Hexane 1:1 eluent) to afford 56 mg (80% yield) (3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylic acid tert-butyl ester as a colorless foam
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)CCC>[F:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: Fc1cccnc1Cl
Solvent: CCCCO
Product: Fc1cccnc1N1CCNCC1
Temperature: 23 °C
Yield: 72.8 %

Procedure:
The product of Example 28A (3.3 g, 0.025 mol) in n-butanol (150 mL) at 23° C. was treated with piperazine (21.5 g, 0.25 mol) and then reflux for 3 days. The reaction mixture was allowed to cool to 23° C. and concentrated under reduced pressure. The residue was slurried with water and ethyl acetate. The ethyl acetate solution was separarted, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 3.3 g (73% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.80 (m, 4H), 3.38 (m, 4H), 6.84 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H); MS (ESI) m/e 182 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(CCO)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)ethanol (1.2 equiv) to give 160 (20.9 mg, M+1 426.1)
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]2[CH2:54][O:53]C(C)(C)[O:51]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:27][O:26][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([CH2:15][O:14][C@H:12]2[CH2:13][NH:8][CH2:9][C@@H:10]([O:48][CH2:49][C@H:50]([OH:51])[CH2:54][OH:53])[C@@H:11]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[CH:25]=1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)CO)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (g) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol as light yellow solid; MS: 633 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12].C(N(CC)CC)C.Cl>CN(C=O)C>[NH2:8][C:7]1[C:4]([C:5]#[N:6])=[C:3]([S:2][CH3:1])[C:13]([C:11]#[N:12])=[C:14]([SH:15])[N:16]=1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: N#CCC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1c(C#N)c(N)nc(S)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 g (58.74 mmol) of 2-(di(methylthio))methylidenemalononitrile and 7.1 g (70.48 mmol) of cyanothioacetamide were initially charged in 21 ml of DMF, and 16.4 ml (117.47 mmol) of triethylamine were added dropwise at room temperature. The mixture was stirred at room temperature for 8 h. The reaction mixture was added to 300 ml of 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried. This gave the product as a powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([CH:16]=[O:17])[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC1CCC(C=O)CC1
Yield: 81.8 %

Procedure:
To a solution of [4-(tert-butyldimethylsilanyloxymethyl)-cyclohexyl]-methanol (8.5 g) obtained in Step 1 in chloroform (85 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane; 15.3 g) under ice-cooling, followed by stirring the mixture under ice-cooling for 2.5 hours. After addition of aqueous sodium sulfite solution and aqueous sodium bicarbonate solution, the reaction mixture was filtered through Celite, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:9) to give 4-(tert-butyldimethylsilanyloxymethyl)-cyclohexanecarbaldehyde (6.9 g).