Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[OH-].[NH4+:16].II>C1COCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:16])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: [NH4+]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Reaction time: 48 h
Yield: 84 %

Procedure:
4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed by iodine (464 g, 1.8 mol). The resulting mixture was allowed to stir for 2 days at which time it was concentrated under reduced pressure. The residue was acidified with HCl (2 N) and extracted into diethyl ether. The organic layer was washed with brine and dried (sodium sulfate) and concentrated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to provide the title compound (166 g, 84%): 1H NMR (DMSO-d6) δ: 11.91 (1H, s), 7.67 (1H, d), 7.20 (1H, d), 3.88 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2([C:33](OC)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.[BH4-].[Li+].C([O-])(O)=O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2([CH2:33][OH:34])[CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4(CO)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-methoxycarbonyl-cyclopent-1-yloxy)-benzyl]-benzene (0.15 g) in dry tetrahydrofuran (3 mL) chilled in an ice-bath is added lithium borohydride (8 mg). The reaction mixture is stirred at ambient temperature for 16 h. Aqueous NaHCO3 solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C.C(OCC)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)(=O)=O)cn3)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(S(C)(=O)=O)cn3)c2)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A partially dissolved mixture of 64.5 g (0.155 mol) of 2-propionyl-3-hydroxy-5-(3-(5-(methylsulfonyl)-2-pyridyloxy)phenyl)cyclohex-2-en-1-one in 200 mL of CH2Cl2 and 700 mL of absolute ethanol was treated with 17.7 g (0.186 mol) of ethoxyamine hydrochloride and 15.3 g (0.186 mol) of sodium acetate. The resulting slurry was stirred for 20 hours at room temperature. The slurry was poured into 3 liters (L) of water and the CH2Cl2 layer was thoroughly removed. The CH2Cl2 layer was dried over MgSO4, filtered and the CH2Cl2 evaporated off to yield a pale oily residue. The residue was passed through a short column of silica gel (about 300 g), eluting with CH2Cl2. Evaporation of the initial 2 L of eluent afforded a pale oil. This oil was dissolved in 400 mL of diethyl ether which briefly formed a clear solution before precipitating the product as a white solid. The product was filtered and dried in vacuo to afford 63.5 g (89 percent of theoretical) of the above indicated product as a white crystalline solid. The product melted at 125.5°-128° C.; 1H NMR (CDCl3): δ1.17 (t, 3H, --N=CCH2CH3), 1.32 (t, 3H, --OCH2CH3), 2.68-3.62 (m includes s at 3.10, 10H, --N=CCH2 --, ring CH2CHCH2 --, CH3SO2 --), 4.18 (q, 2H, --OCH2 --), 7.05-7.58 (m, 5H, ArH's), 8.22 (dd, 1H, ArH), 8.78 (d, 1H, ArH), 15.1 (br s, 1H, enol H) (Compound 3).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[O:16][CH3:17].[Li]CCCC.CN(C)[CH:25]=[O:26]>C1COCC1.O>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: COCOCCc1cc(OC)c(Br)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOCCc1cc(OC)c(C=O)cc1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
In a round bottom flask, 1-bromo-2,5-dimethoxy-4-(2-methoxymethoxy-ethyl)-benzene (0.55 g, 18.02 mmol) was dissolved in 30 mL of dry THF. The reaction mixture was cooled to −78° C. using a dry ice-acetone bath and stirred for 10 min. A solution of n-BuLi (0.86 mL of 2.5 M solution in hexane) was added and the reaction mixture was stirred for an additional 30 min. Dimethyl formamide (0.26 g, 36.06 mmol) was added and then the temperature was allowed warm up slowly to room temperature and stirred for 30 min. The reaction mixture was diluted with water and the organic material was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The crude material was purified by flash column chromatography using a hexane and ethyl acetate gradient to give colorless oil in 56% yield. MS (m/z) 255 (M+1)+. 1HNMR(CDCl3): δ ppm 2.96 (m, 2H), 3.32 (m, 3H), 3.75 (m, 2H), 3.79 (s, 3H), 4.13 (s, 3H), 4.63 (s, 2H), 6.98 (s, 1H), 7.26 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:10]2[C:11](Cl)=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[OH:9])=[C:6]([C:21]([F:24])([F:23])[F:22])[CH:5]=[CH:4][N:3]=1.[O-2].[Mg+2].[H][H]>CO.[Pd].C(Cl)Cl>[F:19][C:16]([F:17])([F:18])[C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][C:6]=1[C:21]([F:22])([F:24])[F:23])[OH:9]
Reactant: OC(c1c(C(F)(F)F)ccnc1Cl)c1c(C(F)(F)F)ccnc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Yield: 80.6 %

Procedure:
To a solution of 1.4 g of 1,1-bis-(2-chloro-4-trifluoromethylpyrid-3-yl)methanol in 12 ml of methanol were added 0.8 g of magnesium oxide and 0.3 g of 5% palladium on carbon. This mixture was then shaken on a Parr hydrogenation apparatus overnight under 50 psi of hydrogen. The palladium catalyst and magnesium oxide were removed via filtration through dicalite, and the methanol filtrate was concentrated in vacuo to afford 1.6 of a yellow solid. This solid was dissolved in 25 ml of methylene chloride. The methylene chloride solution was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.93 g of 1,1-bis-(4-trifluoromethylpyrid-3-yl)methanol as a yellow solid.
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester (71 mg, LC/MS: m/z 878) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to general procedure A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+:29]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O-:26])=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[Na+:29]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1cccc(F)c1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 86 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 6 (4.2 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (3.7 g, 86%) as an amorphous solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: N#Cc1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 30 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 4-(3-chloropropoxy)benzonitrile were reacted using potassium iodide as catalyst to give the white title compound (recrystallizing from isopropyl alcohol-isopropyl ether) in 30% yield, m.p. 107°-108° C.
Reaction SMILES: [CH:1]1[C:10]2C(=CC=[CH:8][CH:9]=2)C=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C@H:15]1[CH2:39][NH2:40])(=[O:13])=[O:12].[C:41]1([CH3:49])[C:42]([CH:47]=O)=[CH:43][CH:44]=[CH:45][CH:46]=1.Cl[Sn]Cl.[BH3-]C#N.[Na+]>CO>[CH3:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:49][NH:40][CH2:39][C@H:15]1[N:14]([S:11]([C:2]2[CH:3]=[CH:8][C:9]3[C:10](=[CH:10][CH:1]=[CH:2][CH:3]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:18][C@H:17]([SH:19])[CH2:16]1
Reactant: Cc1ccccc1C=O
Reactant: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: Cl[Sn]Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CNC[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
250 mg (0.56 mmol) (2S,4R)—C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine and 58 μl (0.5 mmol) o-tolualdehyde in 1 ml MeOH were treated with a solution of 57 mg (0.3 mmol, 0.6 eq) SnCl2 and 38 mg (0.6 mmol, 1.2 eq) NaBH3CN in 1 ml MeOH at room temperature and subsequent cleavage of the protecting group (Method 3) gave (3R,5S)-5-[(2-methyl-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol as white solid, mp 122° C., MS: 427 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NC1CN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
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/[CH:11]=[CH:12]/[C:13](OC)=[O:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[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][CH2:12][CH2:13][OH:14]
Reactant: COC(=O)/C=C/c1ccc2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl(2E)-3-(quinolin-2-yl)prop-2-enoate G5 (2.37 g, 11.1 mmol) dissolved in 100 mL THF was cooled to 0° C. and treated with a 1M solution of LAH in THF (33.3 mL, 33.3 mmol) dropwise over 5 minutes. The reaction was allowed to warm to room temperature and stir overnight. The reaction was then carefully quenched with 1.3 mL of water, 1.3 mL of 15% NaOH, and 3.9 mL of water, Solid Na2SO4 was added and the slurry was stirred for 2 hours, filtered and concentrated by rotary evaporation. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes gradient) to provide 575 mg (27%) of G6 as a brown oil. MS (Electrospray): m/z 188.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].C1C(=O)N([Br:22])C(=O)C1.C(O)(=O)C>C(Cl)Cl>[Br:22][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)=[N:14][CH:13]=1
Reactant: CCOc1ccc(-c2nccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(-c2ncc(Br)s2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 2-(4-ethoxyphenyl)thiazole (1.03 g, 5.00 mmol) in DCM (30 mL) were added NBS (0.98 g, 5.50 mmol) and acetic acid (0.3 mL) with stirring at rt under N2. The reaction was stirred at 48° C. for 3 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (1.34 g, 94%).
Reaction SMILES: [NH:1]([C:29]([CH3:31])=[O:30])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O[N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:29]([CH3:31])=[O:30])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([O:28][N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reaction time: 5 h

Procedure:
A solution of Ac-Ser(tBu)-Asp(OtBu)-Ala-OH (24.7 g, 55.4 mmol) in dry THF (526 mL) was treated with HOSu (9.55 g, 83.1 mmol, 1.5 eq.) and cooled to 0°. To the cold stirring (mechanical) solution DCC (17.14 g, 83.1 mmol, 1.5 eq.) was added portionwise and stirring proceeded at 0° for 30 min at 25° for 5 h. The reaction mixture was filtered and the filtrate evaporated to dryness and crystallized from isopropanol (250 mL). Yield: 23.2 g (77.2%); mp 155°-157°; [α]D25 -41.48° (c 1, MeOH); Rf 0.54 (CHCl3 :MeOH:AcOH; 80-5-1). Anal. calc. for C24H38N4O10 (542.58): C, 53.13; H, 7.06; N, 10.33. Found: C, 53.21; H, 6.85; N, 10.29.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:7][N:6]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N+]=[N-]>N.CO.[Ni]>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:7][N:6]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from Example 174C (2.54 g, 7.05 mmol) in 7 M ammonia-methanol (30 mL) was added to Raney®-nickel 2800 water slurry (2.54 g, 43.3 mmol; washed once with methanol) in a 250 mL stainless steel pressure bottle. The mixture was shaken under 30 psi of hydrogen at room temperature for 4 hours with periodic venting of nitrogen gas. The mixture was filtered through a 0.45 micron nylon filter, and the volatiles were removed in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O:8][CH2:9][CH2:10][CH:11](Cl)[C:12](=O)[CH3:13])(=O)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:11]([CH2:10][CH2:9][OH:8])=[C:12]([CH3:13])[N:4]=1
Reactant: NC(N)=S
Reactant: CC(=O)OCCC(Cl)C(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)sc1CCO
Temperature: 80 °C

Procedure:
2-(2-Amino-4-methyl-thiazol-5-yl)-ethanol was prepared according to general procedures presented hereinabove, by adding 20 grams (0.263 moles) of thiourea to 200 ml of dry toluene, followed by addition of 47 grams (0.263 moles) of 5-acetoxy-3-chloro-2-pentanone over a time period of 20 minutes. The reaction mixture was heated at 80° C. for 24 hours and thereafter approximately 180 ml of toluene were removed by evaporation. 180 ml of water and 20 ml of HCL solution (32%) were then added and the reaction mixture was refluxed for 1 hour at 90° C. The organic phase was then removed by washing with chloroform, and the aqueous phase was turned basic (pH 8-9) using a 5 N solution of sodium hydroxide. The product was extracted once with 70 ml chloroform and once with 70 ml ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvents were removed by evaporation to give 30 grams (72% yield) of violet-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:22](=[O:25])[CH2:23]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:23][C:22]([C:21]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)CCl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: COc1cc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3,4,5-trimethoxy-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound. Rf =0.45 (6% methanol/dichloromethane).
Reaction SMILES: FC1C(O[C:9](=[O:33])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[C:13]([O:31][CH3:32])[CH:12]=2)=C(F)C(F)=C(F)C=1F.[CH:38]1([C:45]2[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=2)[NH2:48])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(OCC)(=O)C>[CH:38]1([C:45]2[CH:46]=[C:47]([NH:48][C:9](=[O:33])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=[O:30])=[C:13]([O:31][CH3:32])[CH:12]=3)[CH:49]=[CH:50][CH:51]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: Nc1cccc(C2CCCCCC2)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1OCCN1C(=O)c2ccccc2C1=O
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(C3CCCCCC3)c2)ccc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3-Methoxy-4-(2-phthalimidoethoxy)phenylacetic acid pentafluorophenyl ester (690 mg) and 3-cycloheptylaniline (500 mg) are dissolved in ethyl acetate (10 ml), and the mixture is heated with stirring at 60° C. for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-(3-cycloheptylphenyl)-3-methoxy-4-(2-phthalimidoethoxy)phenylacetamide (500 mg). This product is dissolved in ethanol (10 ml), and thereto is added hydrazine monohydrate (610 mg), and the mixture is heated under reflux for 2 hours. The insoluble materials are removed by filtration, and the solvent is evaporated under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The organic layer is dried over sodium sulfate, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 30% chloroform/methanol), and treated with 10% hydrogen chloride-methanol to give the desired compound (170 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18](O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.C(OC(N1CCC(COS(C2C=CC(C)=CC=2)(=O)=O)CC1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2nncc(Oc3ccc4[nH]c(C)cc4c3F)c2c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
Under nitrogen a mixture of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (150 mg, 0.44 mmol), (prepared as described in Example 4), 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine (196 mg, 0.53 mmol) and potassium carbonate (122 mg, 0.88 mmol) in DMF (6 ml) was stirred at 100° C. for 2.5 hours. The mixture was filtered, and filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol (99/1 and 95/5). The fractions containing the expected product were combined and evaporated. The residue was triturated with a mixture of pentane/ether (1/1) and the solid was filtered, washed with pentane and dried under vacuum to give 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (100 mg, 42%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][C:26](N(OC)C)=[O:27])[CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH3:21])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:33]1[S:34][CH:35]=[C:36]([Cl:38])[N:37]=1>>[Cl:38][C:36]1[N:37]=[C:33]([C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][N:10]2[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[C:17]3[C:12]([N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[CH:11]2)[S:34][CH:35]=1
Reactant: Clc1csc(Br)n1
Reactant: CON(C)C(=O)CCCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O

Procedure:
The title compound was prepared from 5-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylpentanamide and 2-bromo-4-chlorothiazole by a method similar to Example 13, step 3;