Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N>[Zn]>[Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:17])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: N
Agent: [Zn]
Product: Clc1cccc2cc3cccc(Cl)c3cc12
Temperature: 25 °C

Procedure:
25 g (91 mmol) of 1,8-dichloroanthraquinone and 65 g (1 mol) of Zn dust were suspended in 1 l of a 20% strength by weight aqueous ammonia solution and the mixture was refluxed for 3 hours. After cooling to room temperature, the solid was separated off via a Büchner funnel. The aqueous phase was extracted three times with 150 ml each time of dichloromethane; the solid was extracted a number of times with dichloromethane while being treated with ultrasound. The combined organic phases were dried over magnesium sulfate and freed of the solvent on a rotary evaporator. The solid, whitish yellow residue was suspended in 600 ml of propanol and 65 ml of 12M hydrochloric acid and the mixture was refluxed for three hours. The solvent was subsequently removed under reduced pressure, the residue was taken up in dichloromethane, the solution was washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. Removal of the solvent gave 1,8-dichloroanthracene as a yellow solid which was recrystallized from propanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:25][CH:26]([CH3:33])[C:27]([O:29][CH:30](Cl)[CH3:31])=[O:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:31][CH2:30][O:29][C:27](=[O:28])[CH:26]([CH3:33])[CH3:25])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(Cl)OC(=O)C(C)C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 65 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (13.0 g, 34.3 mmol) dissolved in 300 mL of anhydrous toluene was reacted with 15.4 g (103 mmol) of 1-chloroethyl 2-methylpropanoate (22) in the presence of 23 g (86 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 11 g (65% yield) of the title compound (29a) as a colorless oil. Rf=0.63 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.23 (m, 12H), 1.53 (d, J=5.6 Hz, 3H), 2.24-2.32 (m, 2H), 2.51-2.65 (m, 1H), 3.21-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.83-3.85 (2s, 1H), 3.96 (d, J=9.6 Hz, 1H), 4.20-4.24 (2d, J=8.8, 9.2 Hz, 1H), 4.33-4.37 (2d, J=11.2, 11.6 Hz, 1H), 4.60-4.66 (2d, J=11.6, 11.6 Hz, 1H), 6.91-6.95 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 514.90 (M+Na)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24](C(OCC)=O)[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.Cl>O1CCOCC1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:24][S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(-c3ccccc3)csc2n1-c1ccc(OCCN2CCOCC2)cc1
Yield: 93.8 %

Procedure:
The compound of Example 92 (91 mg, 0.18 mmol) was dissolved in dioxane (1 mL) and 4M HCl(aq) (1 mL) added and the mixture heated at reflux for 48 h. The reaction was partitioned between 2M NaOH(aq) and THF and the combined THF layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0–10% MeOH in EtOAc) to give the title compound as an off-white solid (73 mg, 94%). δH (CDCl3) 7.74 (1H, d, J 9.6 Hz), 7.33–7.28 (7H, m), 7.05–7.01 (2H, m), 6.75 (1H, s), 6.58 (1H, d, J 9.6 Hz), 4.12 (2H, t, J 5.7 Hz), 3.76–3.67 (4H), m), 2.78 (2H, t, J 5.7 Hz), 2.56–2.52 (4H, m). LCMS (ES+) RT 2.46 minutes, 433 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])[CH2:6]Br.[F:9][C:10]([F:33])([F:32])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][CH2:23][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>CN(C)C=O>[F:9][C:10]([F:32])([F:33])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][CH2:23][CH:24]([O:25][CH2:6][C:5]([O:4][CH3:3])=[O:8])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1
Reactant: OC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Sodium hydride (25 mg, 60%) was added to a stirred solution of methylbromoacetate (84 mg) and the compound of Example 3 (200 mg) in dry dimethylformamide (0.5 ml). The mixture was stirred at 23° C. for 18 hrs, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 9:1 hexanes:ethyl acetate to give the title compound as a clear oil. 1H NMR (250MHz, CDCl3) δ3.60-3.68 (1H, m), 3.68 (3H, s), 3.80-3.94 (1H, m), 3.95-4.21 (2H, q), 4.64-4.80 (3H, m), 7.23-7.39 (5H, m), 7.80 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:13][NH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN
Reactant: CCC(=O)c1ccncc1
Solvent: CCO
Product: CCOC(=O)NN=C(CC)c1ccncc1
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.12 gm (0.03 mole) of ethyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled at room temperature and then chilled in the refrigerator to give crystals which are collected, washed with Skellysolve B and dried to yield 3.25 gm (49%) of the title compound having a melting point of 147.1° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C@H:2]1[N:3]([C:8]2[N:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]=23)[CH2:4][CH2:5][N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:7]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2cccnc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2cccnc12

Procedure:
Using methods described in Example 10 and starting with (R)-8-(2-methylpiperazin-1-yl)-5-phenylpyrido[3,2-d]pyridazine 75 (245 mg, 802 μmol), triethylamine (224 μl, 1.60 mmol), and benzoyl chloride (116 μl, 1.00 mmol) afforded (R)-(3-methyl-4-(5-phenylpyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)(phenyl)methanone 76. MS 409.2 (calc'd) 410.2 (M+H, found).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([CH3:10])[CH:4]=1>CC(O)C.[Ni]>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc(N(C)C)cc[n+]1[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: Cc1cc(N(C)C)ccn1
Yield: 90.3 %

Procedure:
A suspension of 4-dimethylamino-2-methylpyridine N-oxide (1.67 g) in 2-propanol (15 ml) was hydrogenated over Raney-nickel (50% suspension in water, 1 ml) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 4-dimethylamino-2-methylpyridine (1.35 g).
Reaction SMILES: [CH2:1]1[CH2:8][O:7][C:3]([CH3:6])([CH2:4][OH:5])[O:2]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>[H-].[Na+].C1C=CC=CC=1>[C:12]([O:5][CH2:4][C:3]1([O:7][CH2:8][CH2:1][O:2]1)[CH3:6])(=[O:13])[CH2:11][C:10]([CH3:9])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CC1(CO)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCC1(C)OCCO1
Yield: 62.8 %

Procedure:
100 mg of 50% sodium hydride was added to a mixture of 20 g of 2,2-ethylenedioxypropanol and 100 ml of benzene, and 20 g of diketene was added dropwise to the mixture while refluxing the mixture. After refluxing the mixture for 2 hours, the solvent was distilled off and the resulting residue was distilled under reduced pressure to obtain 21.5 g (70% yield) of 2,2-ethylenedioxypropyl acetoacetate as a colorless oil having a boiling point of 90° C. (6 mmHg).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:7]2[CH2:8][CH2:9][N:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:6]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCCN1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCN1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.63 g (3.71 mM) of N-[2-(1-piperazinyl)ethan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride and 3.0 ml (21.5 mM) of triethylamine in ethanol (16 ml) was added 0.68 ml (4.47 mM) of 1-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [CH2:1]([C@@H:11]1[CH2:28][C:27]2[CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=[CH:23][C:22]=2[C@@H:21]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:20]2[F:37])([CH3:18])[C:16](=[O:38])[CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:39]([OH:47])(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH2:30]([O:29][C:25]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][C@@H:20]3[F:37])([CH3:18])[C:16](=[O:38])[CH2:15][CH2:14]4)[C@H:11]([CH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:39](=[O:47])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28][C:27]=2[CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCNCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: O=C(O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCN(CCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 59.7 %

Procedure:
A solution of 275 mg of 7α-(5-azadecyl)-3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-one in 7.8 ml of dimethylformamide is stirred with 175 mg of benzoic acid and 250 mg of 1-hydroxybenzotriazole and 0.2 ml of N,N′-diisopropylcarbodiimide for 24 hours at room temperature. Then, the reaction mixture is added to ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 197 mg of N-[4-(3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-on-7α-yl)-butyl)-N-pentyl-benzamide is obtained.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:11]1[N:15]=[C:14]([NH:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[S:13][N:12]=1)[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[Na+:24].Cl>O1CCCC1>[CH2:1]([O:4][N:5]=[C:6]([C:11]1[N:15]=[C:14]([NH:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[S:13][N:12]=1)[C:7]([O-:9])=[O:8])[CH:2]=[CH2:3].[Na+:24]
Reactant: C=CCON=C(C(=O)OC)c1nsc(NP(=O)(OC)OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)[O-])c1nsc(NP(=O)(OC)OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-allyloxyimino-2-(5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (37.3 g) in tetrahydrofuran (106 ml) was added 1N-aqueous sodium hydroxide (234 ml) and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was adjusted to pH 5 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous layer was separated out, adjusted to pH 1.0 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue dissolved in methanol (50 ml) was added dropwise to a solution of sodium acetate (8.7 g) in methanol (90 ml) at ambient temperature under stirring, which was continued for one hour at the same temperature. To the mixture was added ethyl acetate (200 ml) and the resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give sodium 2-allyloxyimino-2-(5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (32.6 g), mp. 168° to 173° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H]1[C@H](c2cnc(C(C)(C)C)nc2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution of ethyl trans-2,2-dimethyl-3-[2-(2-methyl-prop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate (2.6 g) in ethanol (50 cm3) was mixed with a solution of sodium hydroxide (1.0 g) in water (50 cm3) and the mixture stirred at the ambient temperature for 5 hours. After removal of the bulk of the ethanol by evaporation under reduced pressure the pH of the residual mixture was adjusted to 3 with dilute hydrochloric acid. The mixture was extracted with diethyl ether (2×200 cm3), and the combined extracts washed with water and dried over anhydrous magnesium sulphate. Evaporation of the ether under reduced pressure yielded trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylic acid (2.1 g), melting point 168°-9° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccc2cc(N3CCNCC3)ccc21
Yield: 205 %

Procedure:
4-(1-tert-butoxycarbonylmethyl-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.80 g) was treated with a mixture of 60 mL of TFA in 120 mL of methylene chloride overnight at room temperature. At this time, the solvent was removed in vacuo. This resulted in 11.26 g of a light yellow residue. This residue was used without further purification in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:16]2=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]2[CH:14]=[CH:13][CH:12]=1>C1COCC1.CO.[Pt](=O)=O>[CH: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]1[C:16]2=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]2[CH2:14][CH2:13][CH2:12]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4ccccc4c3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc4ccccc4c3)C2=N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.9 %

Procedure:
To a solution of 9-naphthalen-2-yl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF/methanol (30 mL/30 mL) was added platinum (IV) oxide (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (104.7 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)[CH:35]=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:34]([CH3:35])[CH3:33])=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)N(C)C)CC3)nc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid from Example 334 (0.050 g, 0.00011 mol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.137 mmol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrated to give 335, analyzed by rHPLC. MS: (ESI+)=466.3
Reaction SMILES: O.[OH-].[Li+].[CH3:4][SH:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[C:8]=1F.O>CN(C)C=O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[C:8]=1[S:5][CH3:4]
Reactant: CS
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(Cl)ccc(C(=O)O)c1S(C)(=O)=O
Reaction time: 2 h
Yield: 55 %

Procedure:
Lithium hydroxide monohydrate (1.26 g) was added to a solution of methyl mercaptan (0.72 g) in dimethyl formamide. To this mixture was added 4-chloro-3-fluoro-2-(methylsulphonyl)benzoic acid (3.7 g). The mixture was stirred for 2 hours then poured into water and acidified to pH1. It was extracted with ether, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-(methylsulphenyl)-2-(methylsulphonyl)benzoic acid (2.26 g) as a white solid, NMR (CDCl3) 2.5(s,3H), 3.45(s,3H), 7.5(d,1H), 7.7(d,1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1([CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[OH-].[K+]>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:45]2[C:39]3[C:40](=[N:41][CH:42]=[C:37]([O:36][CH2:35][CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:38]=3)[NH:43][CH:44]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C(O)c2c[nH]c3ncc(OCCN4CCOCC4)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 315 mg, 0.828 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine (79, 205 mg, 0.829 mmol, prepared as described in Example 29), and potassium hydroxide (70 mg, 1 mmol) in methanol (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a yellow solid (80, 0.2 g, 40%). MS (ESI) [M+H+]+=628.42.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and D-alanine benzylester p-toluene sulfonic acid salt (1.3 g, 3.5 m mole) were dissolved in DMF (5 ml), and WSC (0.64 ml) was added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order. The mixture was dried with anhydrous sodium sulfate and the thus obtained solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-alanine benzylester material.