Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(C1C=CC(C(O)=O)=C(OC)C=1)(C)(C)C.[Br:30]Br>C(Cl)(Cl)Cl>[Br:30][C:9]1[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1cc(C(C)C)ccc1C(=O)O
Agent: COc1cc(C(C)(C)C)ccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-4-iso-propyl benzoic acid (prepared in an analogous manner to Preparation 37, 4-tert-butyl-2-methoxy benzoic acid) (7.0 g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27 g). m /z (CI): 275, 273 (MH+ ; 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: C=C(C(=O)OCC)c1ccc(Cl)nc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)c1ccc(Cl)nc1OC
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of crude ethyl 2-(6-chloro-2-methoxypyridin-3-yl)acrylate (203 g, 0.84 mol) in MeOH (2 L) was added NaBH4 (63.8 g, 1.68 mol) in portions at 0° C. After addition, the reaction mixture was allowed to warm to r.t. over 2 h. The reaction solvent was removed under reduced pressure. The residue was treated with water and extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether→Petroleum ether:EtOAc=10:1) to afford ethyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (126.5 g 62%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H), 1.44 (d, 3H), 3.88 (q, 1H), 3.95 (s, 3H), 4.13 (q, 2H), 6.89 (d, 1H), 7.46 (d, 1H).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)(=O)[NH2:2]>C(Cl)(Cl)Cl>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)#[N:2]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(N)=O)CC[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Yield: 40.4 %

Procedure:
A solution of 17β-carbamoyl-5α-androstan-3-one (2.4 g.) and polyphosphate ester (12 g.) in chloroform (125 ml.) was refluxed for 24 hours. After removing the chloroform by evaporation aqueous 10% sodium carbonate (100 ml.) was added, the mixture cooled, and extracted with ether. The ethereal extracts were washed with water, dried (MgSO4), filtered and evaporated to afford a buff solid (2.45 g.). Purification by preparative t.l.c. (ethanol/chloroform 1:19) afforded a solid (1.48 g.) which was further purified by passing through a florisil column and crystallisation from dichloromethane/petrol to give title compound (915 mg.) m.p. 150°-152°; [α]D + 89° (c 1.12%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].O.[OH-].[Li+]>CO.O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COC(=O)c1cc(C)cc(CN(C)CCO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CN(C)CCO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2-hydroxyethyl)(methyl)amino]methyl}-5-methylbenzoate (180 mg, 0.72 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (302 mg, 7.2 mmol), and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and concentrated under reduced pressure to provide the title compound. ESI MS m/z 224 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20]CC)=[O:19])[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:24])=[O:25])[C:18]([OH:20])=[O:19])[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (740 mg, 1.82 mmol) in tetrahyrofuran/methanol/water (4:1:1, 18.2 mL) was added lithium hydroxide monohydrate (152 mg, 3.63 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1N in water) and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid as a solid. 674.9 mg.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][C:16]#[C:17][CH2:18][S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CO>[C:21]([O:23][CH3:24])(=[O:22])[CH2:20][S:19][CH2:18][C:17]#[C:16][CH2:15][S:13][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCS
Reactant: COC(=O)CSCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
2 ml of a 30% solution of sodium methoxide in methanol were added to a solution of 2 ml of nonanethiol in a 20 ml methanol/5 ml THF mixture, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 2 g of methyl 7-chloro-3-thia-5-heptynoate in 20 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oil thus obtained was chromatographed on a silica gel column (CH2Cl2/heptane 85/15) providing 2.1 g of methyl 3,8-dithia-5-heptadecynoate in the form of an orange-colored oil (yield 64%).
Reaction SMILES: [S].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=S)[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(O)C>[N:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccc1N
Agent: [S]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCNc1nc2ccccc2[nH]1
Temperature: 52.5 °C
Yield: 43 %

Procedure:
1.79 g (8.28 mmol) of yellow mercuric oxide and 27 mg of flowers of sulfur were added to 1.4 g (4.14 mmol) of 3-(2-aminophenyl)-1-(4-tert-butyloxycarbonylaminobutyl)thiourea (Example 23b) in 30 ml of ethanol and the reaction mixture was heated at 50-55° C. for 3 h. The solid was filtered off with suction and washed with ethanol. The filtrate was concentrated and the product was chromatographed through silica gel (DCM:methanol 9:5, then 9:1). Yield: 43%. MS (ES+): m/e=305.2 ( (M+H)+, 100%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClC(Cl)C>[NH:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9]1
Reactant: c1ccc(CN2CCCC3(Cc4ccccc4O3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)CC1(CCCNC1)O2
Yield: 94.2 %

Procedure:
A solution of 13 g (46 mmole) of 1'-benzyl-2,3-dihydrospiro(benzofuran-2,3'-piperidine) in 100 mL dichloroethane was treated with 7.13 g (5.2 mL, 51 mmoles) of 1-chloroethylchloroformate at room temperature for 1/2 hour. The reaction mixture was concentrated and the residue dissolved in CH3OH and heated to reflux for 1/2 hour. The methanol was evaporated at reduced pressure, and the residue partitioned between ethyl acetate and 1N HCl. The ethyl acetate layer was discarded and the aqueous phase was basified to pH 9 and reextracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 8.2 g product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:18]=[CH:17][C:11](/[CH:12]=[CH:13]/[C:14](O)=[O:15])=[CH:10][CH:9]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:15])=[CH:10][CH:9]=1
Reactant: CNOC
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of oxalyl chloride in dichloromethane (2 M, 100 mL, 200 mmol) was added dropwise to a stirred solution of trans-4-bromocinnamic acid [CAS 1200-07-3] (25.0 g, 110 mmol) and DMF (0.5 mL) in dichloromethane (300 mL) at 0° C. under a dry nitrogen atmosphere. The nitrogen line and cooling bath were removed and the mixture was stirred at room temperature until gas evolution had ceased. Volatiles were removed under reduced pressure, and the residue was redissolved in dichloromethane (200 mL). The resulting solution was added dropwise to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (21.5 g, 220 mmol) and triethylamine (61.4 mL, 440 mmol) in dichloromethane (150 mL) at 0° C. When the addition was complete, the cooling bath was removed and the mixture was stirred overnight at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous 10% citric acid, The organic layer was successively washed with aqueous 10% citric acid, aqueous 3 N sodium hydroxide, and brine. The ethyl acetate solution was then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (65:35 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 3.31 (s, 3H), 3.76 (s, 3H), 7.02 (d, J=15 Hz, 1H), 7.43 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H), MS (DCl—NH3) m/z 270 (M+H)+, m/z 287 (M+NH4)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.BrC[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[O:27]>CC(C)=O.C(OCC)(=O)C>[CH:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]([C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:27])=[CH:33][CH:32]=1)([CH3:36])[CH3:35]
Reactant: BrCCc1ccccn1
Reactant: COc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(NCc2ccccn2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
410 mg (2.97 mmol) potassium carbonate and 150 mg (0.59 mmol) 2-bromoethylpyridine hydrobromide are added to a solution of 160 mg (0.59 mmol) (2-amino-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 ml acetone. The reaction mixture is stirred for 2 days at 90° C., diluted with ethyl acetate and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate) the product is obtained as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+].[OH-].[Na+]>O>[CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: CN1C2CCCCC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CN[C@@H]1CCCC[C@H]1N1CCCC1

Procedure:
A mixture of 7-methyl-7-azabicyclo[4.1.0]heptane (7.0 g, 0.063M), pyrrolidine (17.92 g, 0.25M), water (10 ml) and ammonium chloride (0.16 g) was stirred and refluxed for 21 hours. The solution was cooled and solid sodium hydroxide added and extracted with ether (3×50 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to a brown oil. This was distilled under high vacuum to yield a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccc1Cl
Product: O=C(Cl)c1cnccc1Cl

Procedure:
o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known. Thus, for example, J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride. The reaction of 2-hydroxy-quinoxaline-3-carboxylic acid with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give 2-chloroquinoxaline-3-carboxylic acid chloride is described in Arch. Pharm. 306, 401 (1973). The reaction of 4-chloronicotinic acid with thionyl chloride under reflux to give 4-chloronicotinic acid chloride is described in J. Chem. Soc. (C), 1966, 1816.
Reaction SMILES: Cl[CH:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)[CH3:3].[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(C)=O>O1CCCC1>[CH2:13]([O:20][NH:21][CH:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(Cl)c1cc2ccccc2s1
Reactant: NOCc1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(NOCc1ccccc1)c1cc2ccccc2s1

Procedure:
heating 2-(1-chloroethyl)benzo[b]thiophene with O-benzylhydroxylamine in a solvent such as dimethyl sulphoxide or tetrahydrofuran to give 2-(1-(benzyloxyamino)ethyl)benzo[b]thiophene of formula: ##STR4##
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:17]1[O:19][CH2:18]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: CCCCC(CC)COCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCC(CC)COCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 69.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (4.1 g, 18 mmol), 2-ethylhexyl glycidyl ether (4.4 g, 23,6 mmol) and ethyltriphenylphosphonium bromide (0.37 g) are heated under nitrogen for 5 h at 145° C. and the crude product is chromatographed over silica gel (hexane/ethylacetate 1:1) to afford a colourless liquid 5.2 g (70%).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>C1C=CC=CC=1>[SH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]=[CH:8][C:7]1[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:17]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reactant: Nc1ccccc1S
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=Nc2ccccc2S)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
A solution of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (6.79 g, 0.03 mol) in benzene (50 mL) was added to a solution of 2-Aminothiophenol (3.63 g, 0.03 mol) in benzene (50 mL) and heated at 100° C. in closed glass vessel for 3 days. The solvent was removed in vacuum. The product was obtained as a yellow oil in a quantitative yield.
Reaction SMILES: [CH2:1]([N:3]([C@@H:8]1[CH2:14][CH2:13][CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[C@H:9]1[OH:19])[C:4](=[O:7])[CH2:5]Cl)[CH3:2].[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:3]1[C:4](=[O:7])[CH2:5][O:19][C@@H:9]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12][CH2:13][CH2:14][C@@H:8]12)[CH3:2]
Reactant: CCN(C(=O)CCl)[C@@H]1CCCc2ccccc2[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)CO[C@@H]2c3ccccc3CCC[C@H]21

Procedure:
The residue from Step A was dissolved in 50 ml of dimethyl formamide and added dropwise to a solution of 0.7 g (0.0146 m) of a 50% oil dispersion of sodium hydride in 50 ml of dimethyl formamide with stirring. After stirring one hour, excess sodium hydride was decomposed by the addition of water. The mixture was extracted twice with ethyl acetate and the extract was back washed with water, dilute, cold hydrochloric acid and saturated aqueous sodium bicarbonate solution. After drying (Na2SO4) the ethyl acetate solution was concentrated to dryness in vacuo to provide crude product.
Reaction SMILES: CCOCC.Br[CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][SH:29])[CH3:25]>C(Cl)Cl>[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][S:29][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:25]
Reactant: CCNC(=O)CS
Reactant: CCCCCCCCC#CCC#CCC#CCBr
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCC#CCC#CCC#CCSCC(=O)NCC
Reaction time: 1 h

Procedure:
The ether solution of 1-bromo-2,5,8-heptadecatriyne, prepared according to the above operating procedure, is added dropwise under an inert atmosphere to a stirred solution, at 0° C., of sodium thiolate of N-ethylthioglycolamide prepared according to operating procedure b) above. The mixture obtained is stirred for 1 hour after the addition is finished. The solvents are then removed by evaporation under vacuum. The product obtained is dissolved in 100 cm3 of methylene chloride. The organic phase is washed with water, dried over magnesium sulphate, concentrated and then deposited onto a silica gel column. The expected amide is eluted with a mixture of methylene chloride and ethyl acetate (97-3). After evaporation of the eluent, 6 g of product are isolated and are recrystallized from isopropyl ether. 4 g of N-ethyl 3-thia-5,8,11-eicosatriynamide are obtained in the form of beige crystals having a melting point of 59° C.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([Br:48])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.C(O)C>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([Br:48])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(Br)ccc2CC1
Reactant: [H][H]
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CCO
Product: CCC(=O)N[C@H]1CCc2ccc(Br)cc2[C@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.217 g, 0.881 mmol of Rh), Josiphos SL-J216-2 (0.595 g, 0.926 mmol), and N-(1-benzyl-7-bromo-3,4-dihydronaphthalen-2-yl)propionamide (10.88 g, 29.4 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed ethanol (163 ml) was added, and the mixture was agitated under argon for 30 min at 50° C. The vessel was pressurized with 60 psig of hydrogen and agitated at 55° C. for 14.5 hrs. HPLC analysis indicated 89.4% conversion and 93.8% ee. The mixture was concentrated, and the resulting solid was crystallized from MeOH to yield 7.41 g (yield: 68%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]([CH3:46])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][CH2:36][C:35]([NH:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:46])=[O:45])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(C)CCCNC(=O)CCc1ccccc1O
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Triethylamine (0.62 ml) and octadecyl isocyanate (1.38 ml) were added to a solution containing N-[3-(dimethylamino)propyl]-3-(2-hydroxyphenyl)propanamide (1.00 g) in methylene chloride (10 ml). After being stirred for 3.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform : methanol=30:1 to 10:1), thereby yielding the entitled compound (1.93 g) as white solid.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[I-:10].[Na+]>C(#N)C>[C:1](=[O:9])([O:2][CH:3]([I:10])[CH3:4])[O:6][CH2:7][CH3:8]
Reactant: CCOC(=O)OC(C)Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)OC(C)I
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
3.00 g of 1-chloroethyl ethyl carbonate was dissolved in 90 mL of acetonitrile, to which 13.3 g of sodium iodide was added, and this mixture was stirred for 1.5 hours at 60° C. This mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 4.60 g of ethyl 1-iodoethyl carbonate as orange oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:34])[C:22]=1[N:23]1[CH2:32][C:28]2(OC[CH2:29]2)[CH2:27][CH:26]([NH2:33])[CH2:25][CH2:24]1)=[O:16].C=C1CN(C2N(C)N=CC=2[N+]([O-])=O)CC[C@H](NC(=O)OC(C)(C)C)C1>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:34])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:33])[CH2:27][CH:28]([CH3:29])[CH2:32]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC2(CCO2)C1
Agent: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Product: CC1CC(N)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)C1

Procedure:
In the preparation of 448, tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate was converted to 453. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.41 (s, 1H), 7.61-7.43 (m, 4H), 7.28 (td, J=8.8, 2.0 Hz, 2H), 3.66 (d, J=3.0 Hz, 4H), 3.33-3.01 (m, 3H), 2.96-2.77 (m, 2H), 2.19-1.58 (m, 4H), 1.49 (dd, J=24.1, 11.2 Hz, 1H), 0.86 (dd, J=15.5, 6.8 Hz, 3H). LCMS (ES+) m/z 462 (M+1)