Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:6][N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: CN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
9-Methyl-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (435 mg, 1.62 mmol) was dissolved in dichloromethane (11 mL) and cooled on ice. Trifluoroacetic acid (4 mL) in dichloromethane (5 mL) was added and the reaction mixture was stirred at room temperature for 2 h. Evaporation to dryness, co-evaporation with toluene, ethyl acetate and diethyl ether gave a foam which was dissolved in dichloromethane, and sodium hydroxide (2 N) was added. The aqueous phase was extracted five times with dichloromethane. The combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated to give 214 mg (78%) of 3-methyl-3,9-diaza-spiro[5.5]undecane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:17](=[CH:18][CH:19]=2)[CH2:16][C:6]2([C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]2=[O:15])[CH2:5]3)[CH:22]=1)=[O:28]
Reactant: O=C(c1cc(Cl)ncn1)c1cccc(F)c1F
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)c1cccc(F)c1F
Temperature: 0 °C

Procedure:
70 mg (0.28 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 80 mg (0.28 mmol) (6-chloro-pyrimidin-4-yl)-(2.3-difluoro-phenyl)-methanone and 60 μL DIPEA in 600 μL dimethylsulphoxide were stirred for 1 h at 80° C. After cooling the reaction mixture was combined with approx. 10 mL ice water. The liquid was decanted off and the residue was dissolved in DCM and MeOH. After drying with sodium sulphate the mixture was filtered and the solvent was evaporated down. The residue was triturated with ether, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16](B(O)O)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[C:23]2[CH:31]=[CH:30][N:29]=[CH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:22]2[C:23]3[CH:31]=[CH:30][N:29]=[CH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2cnccc12
Reactant: OB(O)c1cc(-c2ccccc2F)nc2ncccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: Fc1ccccc1-c1cc(-c2ncnc3cnccc23)c2cccnc2n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A slurry of 268 mg (1.00 mmol) 2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 166 mg (1.00 mmol) 4-chloropyrido[3,4-d]pyrimidine, 101 mg (1.20 mmol) sodium bicarbonate and 4.5 mg (0.020 mmol) palladium(II)acetate in a mixture of 4 ml dimethylacetamide and 4 ml ethanol was heated to 80° C. and stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/ethyl acetate as eluent yielding 4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyrido[3,4-d]pyrimidine as colourless crystals; HPLC/MS: 1.91 min, [M+H] 354.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[N:10]1([C:5]2[C:4](=[O:15])[N:16]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)[NH:7][CH:6]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Cc1ccnc(NN)c1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-n3ccnc3)c2=O)c1

Procedure:
200 mg (1.0 mmol) of the compound from Example 42A and 118 mg (1.0 mmol) of the compound from Example 1A are dissolved in 2 ml ethanol and 44 mg (0.2 mmol) camphor-10-sulfonic acid are added. The mixture is heated under reflux for 16 h and then concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid in the water).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C.[OH-].[Na+].Cl>C(OCCCC)(=O)C.O.O1CCCC1.CCCCCC>[CH:10]#[C:9][C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCCCOC(C)=O
Product: C#Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
32.4 g (0.2 mols) of p-acetoxystyrene was dissolved in 120 ml of butyl acetate. To the solution was then added 0.033 g of azobisisobutylonitrile (AIBN) with stirring in a stream of nitrogen at a temperature of 80° C. every 2.5 hours three times in all. Thereafter, the mixture was stirred for 5 hours to undergo polymerization reaction. The reaction solution was then poured into 1,200 ml of hexane to cause the precipitation of a white resin. The resin thus obtained was dried, and then dissolved in 150 ml of methanol. To the solution was added a solution of 7.7 g (0.19 mols) of sodium hydroxide in 50 ml of water. The reaction solution was then heated under reflux for 3 hours to undergo hydrolysis. Thereafter, the reaction solution was diluted with 200 ml of water, and then neutralized with hydrochloric acid to cause the precipitation of a white resin. The resin thus obtained was collected by filtration, washed with water, and dried. The resin thus obtained was dissolved in 200 ml of tetrahydrofuran, and added dropwise to 5 liters of ultrapure water with vigorous stirring to reprecipitate. The reprecipitation procedure was then repeated three times. The resin thus obtained was dried at a temperature of 120° C. in a vacuum drier for 12 hours to obtain a poly(p-hydroxystyrene) type alkali-soluble resin R-1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25]Cl)[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+].[I-].[K+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25][C:27]#[N:28])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(CCl)cs4)ccc3o2)n1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(CC#N)cs4)ccc3o2)n1
Temperature: 0 °C
Yield: 42.3 %

Procedure:
A mixture of 4-tert-butyl-2-{5-{[4-(chloromethyl)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.46 g) , sodium cyanide (0.22 g) and potassium iodide (0.19 g) in methanol (10 ml) was stirred under reflux for 21 hours. After being cooled, the mixture poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-{[4-(cyanomethy)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.19 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH2:5][CH:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18](=O)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:18]([NH:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH:4]3[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]3)=[CH:9][NH:10]2)=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1C(=O)CC(c2c[nH]c3cc(NC(=O)c4ccccc4)ccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3cc(NCc4ccccc4)ccc23)C1
Reaction time: 48 h
Yield: 22 %

Procedure:
A solution of compound 115 (2.28 g, 6.563 mmol) in dry THF (30 mL) was treated with LiAlH4 (2.49 g, 65.636 mmol) portion wise over a period of 45 min. at 0° C. The reaction was brought to room temperature and stirred for 48 h. The reaction was quenched with sodium sulfate decahydrate (8.0 g) followed by careful addition of water (9 mL) at 0° C. and stirred for 30 min. at room temperature. The reaction was diluted with ethyl acetate (50 mL), filtered and washed with ethyl acetate (2×50 mL). The combined ethyl acetate layer was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 5:95 to 1:9) to obtain compound 116 (0.44 g, 22%) as a foam. 1H NMR (DMSO-d6) δ 1.76-1.87 (m, 1H), 2.11-2.23 (m, 1H), 2.27 (s, 3H), 2.36 (t, 1H, J=8.4 Hz), 2.42-2.48 (m, 1H), 2.64-2.71 (m, 1H), 2.90 (t, 1H, J=8.1 Hz), 3.37-3.45 (m, 1H), 4.26 (d, 2H, J=5.7 Hz), 5.88 (t, 1H, J=6.0 Hz), 6.34 (d, 1H, J=0.9 Hz), 6.45 (dd, 1H, J=1.8, 8.4 Hz), 6.72 (d, 1H, J=1.2 Hz), 7.17-7.38 (m, 6H), 10.11 (s, 1H); ESI-MS (m/z, %) 306 (MH+, 100); ESI-HRMS calculated for C20H24N3 (MH+), calculated: 306.1964, observed: 306.1967.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:12]([O:18][C:16](=[O:17])[CH2:15][CH2:14][Br:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCBr
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(CCBr)OCc1ccccc1
Yield: 56 %

Procedure:
A spatula tip full of p-toluenesulfonic acid monohydrate was added to a solution of 3-bromopropionic acid (20.49 g, 0.134 mol) and benzyl alcohol (15 mL, ~15.7 g, 0.145 mol) in benzene (150 mL). A Dean-Stark trap was fitted to the reaction vessel and the solution was held at reflux with overnight stirring. After 16 hr at reflux, the reaction was cooled, washed with saturated sodium bicarbonate, dried (Na2SO4), and concentrated to an oil (28.78 g). Fractional distillation at reduced pressure (0.18 torr) gave the desired product as a colorless liquid (18.49 g, 56%) boiling in the range 99°-109° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Li+].[N+:19]([CH3:22])([O-:21])=[O:20].C(OC(=O)C)(=O)C.C(N(CC)CC)C.[BH4-].[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.CS(C)=O.CO>[N+:19]([CH2:22][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][N:12]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccc(Oc2ccccc2)cn1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.9 %

Procedure:
A mixture of 5-phenoxy-pyridine-2-carbaldehyde (700 mg, 3.5 mmol) described in Manufacturing Example 121-1-3, lithium methoxide (170 mg, 4.6 mmol), nitromethane (280 mg, 4.6 mmol), and methanol (10 mL) was dissolved by irradiating ultrasonic wave for 2 minutes at room temperature, after which the reaction solution was concentrated under a reduced pressure. Acetic anhydride (30 mL) and triethylamine (1.1 g, 11 mmol) were added to the residue, which was stirred for 10 minutes at room temperature, after which the reaction solution was concentrated under a reduced pressure. Ethyl acetate was added to the residue, and the organic layer was separated and washed with saturated aqueous sodium chloride once and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, dimethyl sulfoxide (5.0 mL), acetic acid (0.50 mL), and sodium borohydride (270 mg, 7.0 mmol) were added to the residue, which was stirred for 5 minutes at room temperature. Water and ethyl acetate were added to the reaction solution, and then the ethyl acetate layer was separated and washed with aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The solvent was evaporated under a reduced pressure, and the residue was purified first by silica gel column chromatography (heptane: ethyl acetate=2:1) and then NH silica gel column chromatography (heptane: ethyl acetate=4:1 then 2:1) to obtain the title compound (76 mg, 8.9%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1C=CC=CC=1>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:1]2([CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: ClCc1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1C=Cc2ccccc2C1(Cc1ccncc1)Cc1ccncc1

Procedure:
To a stirred mixture of 2-tetralone (4.4 g, 0.03 mol), 4-picolylchloride hydrochloride (10.82 g, 0.066 mol), and benzyltriethylammonium chloride (1.4 g, 0.006 mol) in 80 ml of benzene was added 1N sodium hydroxide (178 ml, 0.178 mol) dropwise during a period of 1 h. at room temperature. Stirring was continued for another hour. Additional benzene (80 ml) was added, the organic layer was separated, and dried over sodium sulfate. The inorganic salts were filtered off, and to the filtrate was added 5 g of Florisil/(a magnesium silicate adsorbent). The mixture was stirred for 30 min., the solids were filtered off, and the benzene was removed by rotary evaporation. The oily residue was dissolved in the minimum amount of ethanolic HCl (5 ml), and a small amount of acetone was added, whereupon the dihydrochloride salt crystallized out of solution. This salt was collected (1.57 g), redissolved in water, and made basic with potassium carbonate. The solids obtained were air dried (900 mg), and recrystallized from cyclohexane to give 1,1-bis(4-pyridinylmethyl)-2(1H)-naphthalenone as a white solid, 460 mg, m.p. 111°-112°. NMR (200 MHz, CDCl3) δ 1.9 (m, 4H); 3.30 (d, 4H); 6.55 (d, 4H); 6.95 (d, 1H); 7.15 (t, 1H); 7.45 (t, 1H); 7.66 (d, 1H); 8.30 (d, 4H). IR (nujol) 1709 cm-1. Analysis. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.12; H, 6.25; N, 8.61.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)CC(CC(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.500 g, 1.35 mmol), methyl 4-(bromomethyl)benzoate (0.370 g, 1.62 mmol), and potassium carbonate (0.56 g, 4.05 mmol) in DMF (6 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 20:80) to provide methyl 4-[(4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)methyl]benzoate (0.604 g, 86%) as a white amorphous.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=1[Cl:21])(=O)(=O)C.[C-:22]#[N:23].[Na+].O>CS(C)=O>[Cl:21][C:8]1[CH:9]=[CH:10][C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][C:7]=1[CH2:6][C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a stirred solution of 2-chloro-5-(Boc-amino)benzyl mesylate (from step (ii) above) in DMSO was added NaCN (2.9 g; 60 mmol), and the solution was stirred at room temperature overnight. The mixture was poured into water (300 mL) and the water suspension was extracted with ether (4×50 mL). The combined organic layers were washed with water, dried (Na2SO4), and concentrated. After flash chromatography (Si-gel; heptane:EtOAc (8:2)), 5.2 g (65%) of the sub-title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].C(O)C.[OH-].[Na+]>[Fe].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Br)cc1N
Yield: 102.2 %

Procedure:
A slurry of 5-bromo-2-methylnitrobenzene (3.00 g), iron powder (3.11 g), and ammonium chloride (2.97 g), in 3:1 ethanol : water (50 ml) was heated at reflux temperature for 1 hour. The mixture was poured into 10% aqueous sodium hydroxide and filtered through Celite®. The filtrate was then extracted with ethyl acetate, the extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the subtitle compound as an oil (2.64 g).
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Br:10][C:11]1[C:12]([CH2:19]Br)=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17]>CO>[Br:10][C:11]1[C:12]([CH:19]=[O:5])=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cc(C)c(Br)c(CBr)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(Br)c(C=O)n1
Reaction time: 0.33 h

Procedure:
Sodium methoxide (581 mg) was added to a solution of 2-nitropropane (0.982 mL) in methanol (20 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. 3-bromo-2-(bromomethyl)-4,6-dimethylpyridine obtained in Preparation Example 33(1) (1.00 g) was added to the reaction mixture, and the mixture was stirred at 50° C. for five hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (467 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:13]([OH:15])=O)[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:13]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:15])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N[C@H](CC1CCC1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N[C@H](CC1CCC1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.7 g (17.2 mmole) of ethoxycarbonyl-3-cyclobutyl-D-alanine (Example 1, Step D) is dissolved in 60 ml of tetrahydrofuran, cooled to 0° C., then 4.85 g (24.5 mmol) of 2,4,5-trichlorophenol and 5.06 g (24.5 mmol) of dicyclohexyl-carbodiimide are added. The reaction mixture is stirred at room temperature for 2 hours, filtered from the separated dicyclohexylurea and washed with tetrahydrofuran. The filtrate and the washings are pooled and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 25 ml of diethyl ether-petroleum ether mixture (1:1), the insoluble dicyclohexylurea is filtered off and the filtrate is evaporated again [the filtered dicyclohexylurea amounts to 4.9 g (89%) and 0.6 g (11%), respectively]. The oily 2,4,5-trichlorophenyl ethoxycarbonyl-3-cyclobutyl-D-alaninate is dissolved in 40 ml of pyridine and 2.12 g (18.4 mmol) of finely pulverised L-proline is added together with 3.43 ml (24.6 mmol) of triethyl amine. The reaction mixture is stirred at room temperature for 3 hours, then evaporated at a pressure of 2.0-2.5 kPa. The residue is distributed between 50 ml of ethyl acetate and 50 ml of 1M HCl. The organic phase is washed first with 10 ml of 1M HCl then with 2×10 ml of water and is extracted with 3×100 ml of 5% NaHCO3. The pooled hydrocarbonate extracts are acidified to pH3 with 6M HCl and extracted with 3×20 ml of diethyl ether. The ethereal extracts are pooled, washed acid-free with water, dried over anhydrous sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: COc1ccccc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COc1ccccc1Nc1ccccc1

Procedure:
A 1 L three neck flask was charged with 2-methoxyaniline (17.65 g, 143 mmol) , bromobenzene (15 g, 96 mmol), Pd2(dba)3 (1.75 g, 1.91 mmole), S-Phos (1.56 g, 3.82 mmol), sodium tert-butoxide (18.36 g, 101 mmol) and 400 mL of xylene. The reaction mixture was refluxed for 4 hours. The product was isolated by column chromatography (5% EtOAc in hexanes) to yield the desired product. (18 g, 94%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[CH3:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:7][CH:6]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1ccc(OCCCl)cc1
Product: ClCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 90 %

Procedure:
The named compound was prepared as described in Example 17 starting with 4-chloroethoxybenzaldehyde (4.0 g, 22 mmol) and using 2-methylbenzothiazole in place of 2-methylbenzoxazole to give (E)-2-[2-(4-chloroethoxyphenyl)ethenyl]benzothiazole (G) (7.6 g, 90% yield) as a yellow solid, mp 92°-94° C. 1H NMR (CDCl3): δ 8.09-6.85 (m, 10H), 4.23 (t, J=5.2 Hz, 2H), 3.81 (t, J=5.2 Hz, 2H).