Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](C(O)=O)([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)=O>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1(C(=O)O)CCOCC1
Agent: O=C=O
Product: O=C(O)C1CCOCC1
Temperature: 180 °C
Yield: 71.8 %

Procedure:
Oxane-4,4-dicarboxylic acid was taken in a round bottom flask fitted with a reflux condenser and was gradually heated to 180° C. When evolution of carbon dioxide decreased, the reaction was allowed to cool to room temperature. The monoacid thus obtained was purified by distillation (160–165° C. at 22 mm Hg) to yield oxane-4-carboxylic acid (16.1 g, 71.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])=[CH:8][CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)Cc1ccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)cc1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [4-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[ClH:26].[NH2:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(NC(=O)c2c(C)cccc2N)cc1
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of N-(4-methylphenyl)-2-([(1,1-dimethylethoxy)carbonyl]amino]-6-methyl-benzamide (1.67 g, 4.90 mmol) in methanol (4 mL) under an argon atmosphere, is treated with a saturated solution of hydrogen chloride in dioxane (30 mL) and stirred at 180° C. for 210 minutes.
Reaction SMILES: CC(C)(C)C[O:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:9]=1)(=[O:7])=[O:6].[ClH:42]>O1CCOCC1>[ClH:42].[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:10]3[CH:9]=[C:8]([S:5]([OH:7])(=[O:6])=[O:4])[CH:13]=[CH:12][CH:11]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A stirred mixture of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid 2,2-dimethyl-propyl ester (1.27 g, 2.13 mmol), 37% HCl (12.5 ml) and dioxane (12.5 ml) was heated under reflux conditions for 19 h and evaporated to dryness. Diethyl ether (50 ml) was added to the crude product and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to yield 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid hydrochloride as a white solid (1.08 g, 90%). MS (ISN) 524.0 [(M−H)−]; mp 407° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of methyl 4-((methyl(phenyl)amino)methyl)benzoate (400 mg, 1.57 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide (210 mg, 5 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and acidified with concentrated hydrochloric acid (12 N, 5 mL). The mixture was re-dissolved by water (50 mL) and dichloromethane (50 mL). Organic phase was separated and concentrated to give the product 4-((methyl(phenyl)amino)methyl)benzoic acid (200 mg, 53%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]3[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:21][C:20]=1[F:43]>ClCCl>[CH3:37][N:32]1[C:31]2[NH:30][C:29]3[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:28]=3[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:14])=[C:20]([F:43])[CH:21]=3)=[O:26])[CH2:36][C:35]=2[CH:34]=[N:33]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
DIEA (0.08 ml, 0.46 mmol) and cyclopropanecarbonyl chloride (0.013 ml, 0.14 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (57 mg, 0.14 mmol) in dichloromethane (10 ml) at 0° C. The mixture was stirred for 90 min at room temperature then diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (33 mg, 54%).
Reaction SMILES: NC1C=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CCOC([S-])=[S:17].[K+]>>[S:17]1[CH:6]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3]1
Reactant: CCOC(=S)[S-]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Agent: [K+]
Product: CC(C(=O)O)c1ccsc1

Procedure:
diazotation of 2-(4-aminophenyl)propionic acid and subsequent reaction of diazonium salt with potassium xanthogenate to give 2-(4-thiophenyl)-propionic acid;
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Yield: 64.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.202 g, 0.61 mmol) and 4-propoxy-piperidine (79KS66) (0.097 g, 0.67 mmol) in MeCN (½ mL) were reacted according to GP14 to give the title compound (108LM32-29) (0.136 g, 65%). 1H NMR (CDCl3) δ 7.15 (bd, J=7.3 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=13.9 Hz, J=31.6 Hz, CH2), 4.05-3.90 (m, 2H), 3.48 (t, J=7.0 Hz, CH2), 3.28-3.20 (m, 1H), 2.79 (bs, 1H), 2.63 (bs, 1H), 2.27-2.11 (m, 3H), 2.10-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.63-1.52 (m, 4H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.5, 145.4, 128.5, 123.4, 122.3, 116.9, 115.2, 75.0, 69.4, 67.4, 63.2, 52.5, 51.5, 45.0, 31.6, 31.5, 29.1, 23.1, 16.6, 10.5; HPLC-MS (ammonium acetate) [M+H]+=347.3.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:43]2[N:44]=[C:45]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:46]3[S:51][C:50]([CH2:52][N:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)=[C:49]([CH3:59])[C:47]=3[N:48]=2)=[CH:37][N:36]=1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>>[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:43]2[N:44]=[C:45]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:46]3[S:51][C:50]([CH2:52][N:53]4[CH2:58][CH2:57][N:56]([C:66](=[O:70])[C@@H:67]([OH:68])[CH3:69])[CH2:55][CH2:54]4)=[C:49]([CH3:59])[C:47]=3[N:48]=2)=[CH:37][N:36]=1
Reactant: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)c(OC)n1
Reactant: C[C@H](O)C(=O)O
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)c(OC)n1

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 2,4-dimethoxypyrimidin-5-yl-5-boronic acid via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 2-(2,4-dimethoxypyrimidin-5-yl)-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was reacted with L-Lactic acid via General Procedure B to give 17.2 mg of 406 after reverse phase HPLC purification. MS (Q1) 544.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O1CCCC1.O>O1CCCC1.CCOCC>[NH2:8][CH2:7][C@H:6]([C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(Cl)cc1)[C@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 112 g (0.4 mol) of rac-(2S*)-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanone in 1 l of dry tetrahydrofuran is added dropwise under argon to a suspension of 39 g (1.03 mol) of lithium aluminium hydride in 1 l of dry tetrahydrofuran so that the temperature does not exceed 50°, whereupon the reaction mixture is stirred at 50° overnight. After cooling to room temperature the reaction mixture is treated with 50 ml of ethanol and subsequently with 200 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The oil obtained is dissolved in 1 l of ether and the solution is left to stand at room temperature overnight. The separated colourless crystals are filtered off under suction, there being obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-chlorobenzyl]cyclohexanol of m.p. 108°-110°. The rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-chlorobenzyl]cyclohexanol hydrochloride prepared from the base in the usual manner is recrystallized from ethanol/ether and melts at 259°-260° (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1.FC(F)(F)C(O)=O.[CH3:49][S:50]([OH:53])(=[O:52])=[O:51]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:49][S:50]([OH:53])(=[O:52])=[O:51].[CH3:17][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)OC(C)(C)C)c(F)c2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl 3-{4-[({2′,6′-dimethyl-4′-[2-(2-oxopyrrolidin-1-yl)ethoxy]biphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (0.51 g, 0.91 mmol) in toluene (5 mL) was added trifluoroacetic acid (5 mL) under stirring at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/methanol=10/1) to give a colorless amorphous powder. The obtained amorphous powder was dissolved in ethyl acetate, and methanesulfonic acid (0.82 mL) was added. The precipitated crystals were collected by filtration, washed, and dried to give the title compound (0.44 g, yield 88%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]2)=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a vial containing tert-butyl {(3S)-1-[5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (719.5 mg, 1.434 mmol), iron powder (793.6 mg, 14.21 mmol) and NH4Cl (1147.6 mg, 21.454 mmol), EtOH (10.00 mL) was added followed by water (2.00 mL). The mixture was stirred at 80° C. for 2 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The pad was eluted with 10% aq. K3PO4 (50 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark solid (491.8 mg, 73%). LCMS calc. for C23H30N5O4S (M+H)+: m/z=472.2. found 472.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH:26]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([S:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=S(=O)(Cl)C1CCCCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)C4CCCCC4)cc3)ccc2C1=O

Procedure:
The compound of example 302 was prepared analogous to compound of example 284 by reaction of compound of example 223 with cyclohexyl sulfonyl chloride. The compound of example 302 was used directly without isolation, for the preparation of compound of example 303.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10]N=C2CCCCC2=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].OS(O)(=O)=O.[C:24]([O-:27])([O-])=O.[Na+].[Na+]>CC#N>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[C:2]1[CH2:7][CH2:6][CH2:5][C:24](=[O:27])[C:3]=1[NH:10]2
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCC1=NNc1cc(Cl)c(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 16 %

Procedure:
2-(2-(3,4,5-Trichlorophenyl)hydrazono)cyclohexanone (1 g, 3.2 mmol) was dissolved in MeCN (10 mL) and aqueous H2SO4 (0.5 mL, 1.8M solution) was added. The reaction mixture was heated to 80° C. for 6 h, basified with saturated Na2CO3 and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound (0.15 g, 16%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 12.3 (bs, 1H), 7.58 (s, 1H), 3.24 (t, J=12.0 Hz, 2H), 2.59 (t, J=13.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[CH3:13]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na]
Product: CCOc1ccc([N+](=O)[O-])cn1

Procedure:
To anhydrous ethanol (250 ml) were added sodium (2.25 g, 97.8 mmol) then 2-chloro-5-nitropyridine (15 g, 9.46 mmol) under argon. The resulting mixture was heated at reflux for 10 hrs. After cooling slightly, the mixture was filtered to remove undissolved particles. The filtrate was condensed by rotary evaporation. The residue was triturated with abs ethanol (50 ml). The solid was collected by filtration and dried giving 13.5 g of the product: mp 90-92° C. mass spectrum (electrospray, m/e): 169 (M+H); IR cm−1: 1600, 1508, 1378, 1290, 1118, 1027; H-NMR δ(CDCl3): 1.431 (3H, t, CH3), 4.512 (2H, q, CH2), 6.800 (1H, d, C3-H), 8.337 (1H, dd, C4-H), 9.068 (1H, d, C5-H). See: Friedman et. al., J. Amer. Che. Soc., 69, 1947, 1204.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]([CH2:36][CH:37]=[CH2:38])[CH:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1.O([CH2:47][CH3:48])S(C(F)(F)F)(=O)=O.[Cl-].[NH4+]>O1CCCC1.O.N1C=CC=CC=1>[CH2:47]([C:20]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)[CH:19]([CH2:36][CH:37]=[CH2:38])[C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][O:12][CH3:11])=[CH:16][CH:17]=2)[O:22][C:21]1=[O:25])[CH3:48]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: C=CCC1c2ccc(OCOC)cc2OC(=O)C1c1ccc(OCOC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCC1c2ccc(OCOC)cc2OC(=O)C1(CC)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
A 1M solution of lithium hexamethyl-disilazide in tetrahydrofuran (86.2 ml) was added dropwise to a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one (16.57 g) in dry tetrahydrofuran (86.2 ml) at −78° C. over 30 minutes under nitrogen atmosphere, followed by stirring for 20 minutes at 0° C. After the reaction mixture was cooled to −78° C., ethyl triflate (21.6 ml) was added dropwise thereto over 20 minutes and the resulting mixture was warmed to −30° C. over 3 hours, followed by addition of pyridine (13.9 ml). This mixture was stirred for 15 minutes at −30° C., cooled to −78° C., and further mixed with saturated aqueous ammonium chloride (100 ml) and water (50 ml). After extraction with ethyl acetate, the organic layer was washed with 0.05 N aqueous hydrochloric acid and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting oil was purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=5/1→4/1) to give (3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one (14.98 g, Yield 84.3%) as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[CH:10]1>CC#N>[Cl:1][C:13]1[N:9]=[CH:10][NH:11][C:12]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]cn1
Solvent: CC#N
Product: COC(=O)c1[nH]cnc1Cl
Reaction time: 12 h
Yield: 15.8 %

Procedure:
N-chlorosuccinimide (0.318 g, 2.4 mmol) was added to a stirred solution of methyl 1H-imidazole-4-carboxylate (0.300 g, 2.4 mmol) in CH3CN (16 mL). The reaction mixture was stirred for 12 h in the dark and then concentrated. The white residue was taken up in EtOAc, satd. aqueous Na2S (10 mL) was added and the solution was stirred for 15 min. The organic layer was isolated, dried (Na2SO4), concentrated and the crude product was purified by column chromatography (20-70% EtOAc/hexanes) to afford the title compound (0.061 g, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H), 7.85 (s, 1H), 3.81 (s, 3H). ES-LCMS: m/z 160.9, 162.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]O)[CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OCc1cccnc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2cccnc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
In a manner similar to that described in Example H, the product from Example G ((S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)-propionic acid tert-butyl ester) (4.39 g, 9.50 mmol) and 3-pyridylcarbinol (0.92 mL, 9.50 mmol) were converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: ClCCCBr
Product: ClCCCSc1cccc(Br)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-bromobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH2:6]1.[OH-].[Na+]>CO>[F:29][C:27]([F:28])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]2[C@@H:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=3)[CH2:9][C@@H:5]([CH2:4][C:3]([OH:31])=[O:2])[CH2:6]2)=[CH:22][CH:23]=1
Reactant: COC(=O)CC1CC(c2ccc(C(F)(F)F)cc2)N(Cc2ccc(C(F)(F)F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@@H]1C[C@H](c2ccc(C(F)(F)F)cc2)N(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C

Procedure:
The ester from Step 5 (240 mg, 0.53 mmol) was dissolved in methanol (2 mL) and NaOH (0.67 mL, 2.65 mmol) was added. The mixture was heated at 60° C. for 2 h. then cooled, evaporated, neutralised with HCl (aq.) and extracted into CH2Cl2. The organic extracts were pooled, washed with water, brine and dried (MgSO4) and evaporated. The residue was purified on silica using 10-100% ethyl acetate in iso-hexane as eluant.