Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3(O)[CH2:12][CH2:13][C@@H:14]2[CH3:24])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1.Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C@@H:14]2[CH3:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C)CC[C@]32O)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2.5 h
Yield: 94.9 %

Procedure:
To a solution of 5.0 g of 3β-acetoxy-14β-hydroxy-17β-methyl-5β-androstane (VIII-a) in pyridine (100 mL), 3.5 g of thionyl chloride were added at 0° C. The solution was stirred at the same temperature for 2.5 hrs and then poured in 100 mL of 1N HCl and crushed ice: the mixture was extracted with ethyl ether: the organic layer was washed with a saturated aqueous solution of disodium hydrogen phosphate, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 4.5 g of 3β-acetoxy-17β-methyl-5β-androst-14-ene as a white solid.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([Cl:14])=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26](=[O:38])[N:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:28]([CH3:31])[C:29]=3[CH3:30])=[O:24])=[CH:18][C:17]=2[F:39])[CH:11]=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CO.O>[C:1]([NH:4][C:8]1[C:13]([Cl:14])=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26](=[O:38])[N:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:28]([CH3:31])[C:29]=3[CH3:30])=[O:24])=[CH:18][C:17]=2[F:39])[CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of N-(4-((2-(N-acetylacetamido)-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (259 mg, 0.47 mmol) in CH3OH (20 mL) was added a solution of Na2CO3 (59.8 mg, 0.56 mmol) in H2O (1 mL). After stirring at rt for 15 minutes, the mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (CH3OH/EtOAc (v/v)=1/50) to give the title compound as a beige solid (160 mg, 66.7%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:23])[C@H:4]([NH:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1)=[O:10])[C:5]([OH:7])=O.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:5]([C@@H:4]([NH:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)=[O:10])[CH:3]([CH3:2])[CH3:23])=[O:7])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(NC(=O)N[C@H](C(=O)O)C(C)C)c2ccccc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(NC(=O)N[C@H](C(=O)N2CCC(Cc3ccccc3)CC2)C(C)C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-3-methyl-2-[3-(2-methyl-quinolin-4-yl)-ureido]-butyric acid hydrochloride (337.8 mg, 1 mmol), 4-benzylpiperidine (175.3 mg, 1 mmol), HOBt (183 mg, 1.2 mmol) and TEA (0.35 mL, 2.5 mmol) in DMF (10 mL) is added EDC (230.0 mg, 1.2 mmol). The mixture is stirred for 15 h at room temperature and then quenched with sat. aqueous Na2CO3 (30 mL). The aqueous phase is extracted with CH2Cl2 (3×20 mL). The combined extracts are dried (Na2SO4), filtered and evaporated. The residue is purified by flash chromatography (SiO2, CH2Cl2/MeOH, 5/1) to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH:21][C:22](=[O:28])[CH2:23][C:24]([O:26]C)=[O:25])=[CH:16][C:15]=3[CH3:29])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH:21][C:22](=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][C:15]=3[CH3:29])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Yield: 47.7 %

Procedure:
50 mg of methyl 3-({4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethyl-phenyl}-amino)-3-oxo-propanoate (Example 1) are stirred in 2 ml of ethanol with 30 mg of sodium hydroxide for 30 minutes. The solvent is removed in vacuo. The mixture is taken up in ether/water, the organic phase is dried and the solvent is removed in vacuo. 23 mg (46%) of 3-({4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylphenyl}amino)-3-oxopropanoic acid are obtained.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccc(OC)cc3)cccc2c1O
Product: COc1ccc(Oc2cccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c23)cc1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[C:5]([N+]([O-])=O)[CH:4]=1>O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([OH:10])=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: Cl
Solvent: O
Product: Cc1cc(O)ccc1Cl

Procedure:
To 160 ml of methanol, there were added 37.9 g of the 4'-chloro-5'-methyl-2'-nitrophenyl methanesulfonate as obtained in the above (ii) and 80 ml of a 7N aqueous solution of sodium hydroxide, followed by heating under reflux for 20 minutes. After cooling, the reaction mixture was poured into 500 ml of water and neutralized with hydrochloric acid. The crystals thus precipitated were filtered and recrystallized from acetone to give thereby 10.4 g (55 mmol) of 4-chloro-5-methyl-2-nitrophenol as yellow crystals. The yield from 4-chloro-3-methylphenol was 31%.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:5][CH:4]=1>Cl>[ClH:1].[ClH:1].[N:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCN1CCNCC1c1ccncc1
Agent: Cl
Product: O=C(O)CCCN1CCNCC1c1ccncc1
Temperature: 100 °C
Yield: 150 %

Procedure:
A mixture of the product of step (i) (5 g) and conc. HCl (50 ml) was heated at 100° C. for 45 min. The resultant solution was evaporated to dryness and the residue dissolved again in conc. HCl and heated to 100° C. for a further 45 min. The reaction mixture was evaporated to dryness, and the residue was twice triturated with toluene, and evaporated to dryness, collected and washed with ether. The crude product was crystallised from hot methanol/ether to give 4-[(4-pyridyl)piperazin-1-yl]butyric acid, dihydrochloride as an off-white crystalline solid (3.45 g): m.p. 280°-300° C. (dec); NMR (d6 -DMSO) δ 2.00 (2H, m), 2.36 (2H, t), 3.12 (2H, m), 3.00-3.70 (4H, v. br, m), 3.50-4.50 (4H, v. br, m), 7.30 (2H, d), 8.35 (2H, d), 12.2 (1H, v. br); m/Z 250 (M+H)+ ; calculated for C13 H19N3O2. 2.0 HCl. 0.5 H2O: C, 47.1%; H, 6.69%; N, 12.7%; found: C, 47.5%; H, 6.7%; N, 12.5%
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14](O)[CH3:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:14]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH3:15]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Boc-D-alanine (5.0 g, 26.4 mmol), dimethylaminopyridine (161 mg, 1.3 mMol), and ethanol (1.34 g, 29.1 mMol) were dissolved in methylene chloride (300 ml), and the solution was cooled to 0° C. To this solution was added 1,3-dicyclohexylcarbodiimide (6.0 g, 29.1 mMol). The mixture was allowed to slowly come to room temperature, and stirred under nitrogen overnight, during which time a white solid precipitated. The precipitate was removed by filtration, rinsed with methylene chloride, and the filtrate was concentrated to a pale yellow oil. Flash chromatography in 10-30% EtOAc/Hexanes yielded 4.9 g of a colorless oil as product. NMR (300 MHz, CDCl3) δ 5.05 (b, 1H), 4.28 (q, 1H, J=7 Hz), 4.20 (q, 2H, J=7 Hz), 1.45 (s, 9H), 1.38 (d, 3H, J=7 Hz), 1.28 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[S:28]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:27]([NH:26][CH3:25])=[S:28])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CN=C=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
N-{2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) and methylisothiocyanate (0.3 ml, 4.4 mmol) were dissolved in THF and the reaction mixture was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and washed with 1N HCl, 10% sodium bicarbonate, water, and brine. The solvents were removed in vacuo and the crude product was purified by flash chromatography (ethyl acetate-methanol, 97:3) to give 1-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3-methyl-2-thiourea (265 mg, 73%) as a solid, mp 135° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[N:17](C)[CH:13]2[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:1][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1
Reactant: CN1C2CCC1C1CCC2N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1C2CCC1C1CCC2N1

Procedure:
To a cold (0° C.) solution of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane (J. Med. Chem. 2000, 43, 2115-2123) and TEA in an DMF (1-2 ml) was added MeI. The mixture was allowed to warm to rt and stirred for 2-3 h. The rxn mixture was evaporated to dryness and partitioned between ether and satd. NaHCO3 and ether layer separated, washed with brine and dried (Na2SO4). Evaporation of ether afforded 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane as a light-brown oil. A stirred suspension of 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane in EtOH containing conc. HCl (0.5 ml) and 10% Pd—C was hydrogenated under balloon pressure of hydrogen overnight. The suspension was filtered and filtrate was added dry toluene (10-15 ml) and evaporated to dryness to afford the 9-methyl-9,10-diazatricyclo[4.2.1.12,5]decane and isolated as bis-HCl salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:17]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)([CH3:15])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(-c2cncc(Br)c2)cc1
Reactant: ClCCOCCCl
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(-c2cncc(Br)c2)cc1)N1CCOCC1

Procedure:
A mixture of 1-[4-(5-bromo-pyridin-3-yl)-phenyl]-1-methyl-ethylamine (Intermediate 229) (1 eq, 1.72 mmol, 500 mg), TEA (3.5 eq, 6.01 mmol, 608 mg), and 2-chloroethyl ether (Sigma-Aldrich, St. Louis, USA) (4 eq, 6.87 mmol, 0.8 ml) in DMF (10 ml) is heated using microwave radiation at 150° C. for 1 h. The mixture is concentrated under reduced pressure, then sat. aqueous NaHCO3 solution is added, followed by extraction with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification or the crude mixture by column chromatography (hexane/EtOAc) gives the title compound; [M+H]+=361/363.
Reaction SMILES: [CH3:1][C:2]1([NH:18][C:19](=[O:21])[CH3:20])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([NH:18][C:19](=[O:21])[CH3:20])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC(=O)NC1(C)CCCN(c2c([N+](=O)[O-])cnn2C)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)NC1(C)CCCN(c2c(N)cnn2C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of N-(4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (330 mg, 1.11 mmol) in a mixture of EtOH (25 mL) and water (2.5 mL) was added ammonium chloride (300 mg, 5.55 mmol) and iron powder (250 mg, 4.44 mmol). The reaction mixture was heated at 100° C. for 2 hr before being cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (40 mL) and the organic layer was separated, washed with brine (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-yl)acetamide as a brown solid which was used without further purification. Following the procedure for Example 149 using this intermediate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 378 as an off-white foam (54 mg, 19% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.86 (s, 1H), 7.39-7.29 (m, 1H), 7.07-6.99 (m, 2H), 6.15 (s, 2H), 5.38 (s, 1H), 3.74 (s, 3H), 3.30-3.18 (m, 4H), 3.12 (ddd, J=13.6, 6.6, 3.1 Hz, 1H), 2.30-2.19 (m, 2H), 2.00-1.72 (m, 6H), 1.45 (s, 3H). LCMS (ES+) m/z 504 (M+1)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C:10]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(CC)CC)C>ClCCl>[C:45]([O:43][CH2:42][C@:11]12[O:24][C@:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)([O:13][CH2:12]1)[C@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]2=[O:44])(=[O:47])[CH3:46]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of (1S,3R,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-one 28g (13.4 g, 21.8 mmol) in dichloromethane (40 mL) were added acetic anhydride (3.0 mL, 32.7 mmol) and triethylamine (6.0 mL, 43.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with water (100 mL). The resulting mixture was extracted with dichloromethane (100 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 28h as a pale yellow solid (12.1 g, 84.6%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.29 (m, 4H), 7.24 (m, 3H), 7.19 (s, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 6.99 (d, 2H), 6.76 (m, 2H), 6.68 (d, 2H), 4.94 (d, 1H), 4.58 (d, 1H), 4.47 (d, 1H), 4.37 (d, 1H), 4.31 (m, 2H), 4.07 (d, 1H), 3.95 (m, 3H), 3.88 (m, 5H), 1.97 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:23]([NH2:46])=[N:24][C:25]([O:41][CH2:42][CH:43]([F:45])[F:44])=[C:26]([CH:40]=1)[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]1)=[O:28].C(Cl)CCl>CC#N>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:46][C:23]3=[N:24][C:25]([O:41][CH2:42][CH:43]([F:45])[F:44])=[C:26]([C:27](=[O:28])[NH:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([C:36]([F:38])([F:37])[F:39])[CH2:34][CH2:35]4)[CH:40]=[C:22]3[N:21]=2)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl

Procedure:
The title compound is prepared from (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (3.15 g, 9.45 mmol), 5,6-diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (3.60 g, 9.42 mmol), EDC (2.0 g, 10.4 mmol) in MeCN (40 ml) in analogy to example 5c.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:2]1=2.C1C=CC2N(O)N=[N:20]C=2C=1.N.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH2:20])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (3.54 g) in DMF (80 mL) were added HOBt-NH3 (4.48 g) and EDCI HCl (5.65 g) at room temperature. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with hexane to give the title compound (1.10 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:2].N.[H][H]>C(O)(C)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8]
Reactant: [H][H]
Reactant: CCP(=O)(CCC#N)OC(C)C
Agent: [Ni]
Agent: N
Solvent: CC(C)O
Product: CCP(=O)(CCCN)OC(C)C

Procedure:
To 34.1 g of isopropyl 2-cyanoethyl(ethyl)phosphinate in 500 ml of isopropanol are added 60 ml of liquid ammonia and 6.8 g of Raney-Nickel. The mixture is heated to 80° and treated with hydrogen at 100 bar. After 11/2 hours hydrogen-uptake stops. The reaction mixture is filtered and the filtrate distilled to give isopropyl 3-aminopropyl(ethyl)phosphinate as a colorless oil, b.p. 75°/13 Pa.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[C:5]=1[OH:15].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:29]>>[CH:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[C:5]=1[OH:15])=[O:29]
Reactant: CS(=O)(=O)c1cc(Cl)cc(CN)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CS(=O)(=O)c1cc(Cl)cc(C=O)c1O

Procedure:
2.4 g (0.009 mol) of 2-aminomethyl-4-chloro-6methylsulfonylphenol hydrochloride are reacted with 1.6 g of urotropine in 18 ml of trifluoroacetic acid to give 2-formyl-4-chloro-6-methylsulfonylphenol in analogy to Example 1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=[C:2]([OH:1])[C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]([OH:10])[C:11](=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:14]([Cl:13])[CH:15]=1)[OH:12]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: OC(=Cc1ccc(Cl)c(Cl)c1)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1

Procedure:
Bis(3,4-dichlorobenzylidene)sorbitol was prepared from aqueous sorbitol and 3,4-dichlorobenzaldehyde according to the method of Example 1. The melting point of the product was 270° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]1([CH3:26])[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([CH3:26])=[CH:13][CH:14]=3)=[CH:24][CH:23]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: COc1ncc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1CNc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine-3-carbaldehyde (0.87 g, 4.03 mmol) in dry MeOH (15 mL) was treated with 4-p-tolyloxy-phenylamine (0.88 g, 4.43 mmol) and reflux for 2.5 h. The solution was cooled to 0° C. and treated slowly with NaBH4 (0.38 g, 10.1 mmol). The reaction stirred at room temperature overnight. Additional NaBH4 (0.38 g, 10.1 mmol) was added and the reaction was continued stirring for additional 6 h. The solvent was removed and the residue was partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic portion was brought to the usual work-up to give a crude material. The product was yielded after chromatography purification (silica gel, 25% EtOAc/hexanes). MS (EI) 399, 401 (M+H)+.