Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[CH:13]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccn2cc(CCl)nc2c1
Reaction time: 2.5 h
Yield: 1.8 %

Procedure:
A mixture of 2-amino-4-picoline (Aldrich; 500 g), 1,3-dichloroacetone (Aldrich; 5.89 g), and 1,2-dimethoxyethane (Aldrich; 44 mL) is stirred for 25 min at 53° C., at which time ethanol (47.5 mL) is added. After stirring for 2.5 h at reflux, the mixture is concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate and brine. The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane (1/99 to 2/98) to give, after crystallization from dichloromethane/hexane, 3.06 g of product. A portion of this material is dissolved in dichloromethane and refluxed with activated charcoal for 30 min. The activated charcoal is removed by filtration through a pad of diatomaceous earth and the filtrate is atmospherically concentrated, at which time hexane is added. The resulting solids are filtered, washed with hexane, and vacuum dried to give 0.15 g of 2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine; mp 250° C. (decomp); ms m/z 180, 182; IR (mineral oil) 774, 1649, 1504, 1252, 701 cm-1 ; 1H NMR (CDCl3) δ 2.39, 4.75, 6.63, 7.32, 7.53, 7.95.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O>[C:44]1([S:50][C:2]2[CH:34]=[CH:33][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([CH3:25])[CH3:24])[C:10]=4[OH:32])[N:8]=[C:4]3[CH:3]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
To a stirred mixture of 75 g of 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and 105 g of N-methylpyrrolidone heated at 90° C. is added first 44.3 g of 45% aqueous potassium hydroxide solution over a 15-minute period then 20.4 g of thiophenol over another 15 minutes. The reaction mixture is then heated at 170-175° C. for four hours with water being removed by distillation. After cooling to 100° C., xylene and water are added and the resultant mixture is made acidic with 15% aqueous hydrogen chloride solution. The organic layer is separated and washed with water and then concentrated. The crude product residue is recrystallized from methanol to yield 82 g of the title compound as a pale yellow solid melting at 124-125° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CCCI
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methylsulfonyl)phenyl]piperidine (0.41 g, 1.62 mmol), acetonitrile (40 ml), potassium carbonate (0.53 g, 4.8 mmol) and 1-iodopropane (0.127 ml, 1.62 mmol). Yield: 0.238 g (50%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 233-235° C. MS m/z (relative intensity, 70 eV) 295 (M+, 4), 267 (17), 266 (bp), 129 (13), 115 (14).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.O>CN(C=O)C>[C:1]1([N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 17.0 g (88.1 mmol) of tert-butyl phenylcarbamate in 150 ml of hexanes 35.2 ml (88.1 mmol) of 2.5 M nBuLi in hexanes was slowly added at gentle reflux for ca. 15 min. This mixture was stirred for additional 30 minutes and then evaporated to dryness. The resulting white powder was added to a solution of 30.6 g (88.1 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 300 ml of DMF. This mixture was stirred for 20 minutes at 75° C. and then poured into 1200 cm3 of cold water. The product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed by 2×300 ml of water, dried over MgSO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol. then 10:1, vol.). Yield 28.0 g (69%) of yellowish oil. Anal. calc. for C28H34BNO4: C, 73.21; H, 7.46; N, 3.05. Found: C, 73.12; H, 7.62; N, 3.24. 1H NMR (CDCl3): 8.19 (m, 1H, 8-H in naphthyl), 7.85 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.77 (m, 1H, 5-H in naphthyl), 7.60 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.40 (m, 1H, 6-H in naphthyl), 7.20 (m, 2H, 3,5-H in Ph), 7.13 (m,\2H, 2,6-H in Ph), 7.08 (m, 1H, 4-H in Ph), 5.21 (s, 2H, CH2N), 1.42 (s, 9H, tBu), 1.38 (s, 12H, CMe2CMe2).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=2)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([NH:23][C:24]3[S:25][C:26]([O:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=4)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=3)=[O:16])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(O[C@@H]1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COC(=O)c1cc(Oc2cnc(N)s2)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)ccc1C
Yield: 85.5 %

Procedure:
The compound of example A3 was obtained by similar method described in example A2 using 2-(4-Cyclopropanesulfonyl-phenyl)-2-[(R)-(tetrahydro-furan-3-yl)oxy]-acetic acid (preparation 5, 0.200 g, 0.613 mmol), methyl 5-(2-aminothiazol-5-yl)oxy-2-methyl-benzoate (preparation 26; 0.194 g, 0.736 mmol), HOBt (0.099 g, 0.736 mmol), and EDCl (0.140 g, 0.736 mmol), N-methyl morpholine (0.0154 g, 1.53 mmol) in DCM (8 mL) to provide the title compound (0.3 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([OH:24])=O)[N:19]([CH3:21])[N:20]=1.[N:25]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([CH2:32][CH2:33][OH:34])[CH2:26][CH2:27]2)=[O:24])[N:19]([CH3:21])[N:20]=1
Reactant: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Reactant: OCCN1CCCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)N1CCCN(CCO)CC1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 16D], 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (Example 12C]) and 2-(1,4-diazepan-1-yl)ethan-1-ol with DCC and catalytic amount of DMAP gave the title compound in 32% yield as white foam. MS: 445.1 (MH+).
Reaction SMILES: O1CCCCC1O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15].O1CCN(C2CCCC=2)CC1.[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C>C1C=CC=CC=1>[OH:32][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:8][CH2:9][C:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]=1
Reactant: O=C1CCCC1
Reactant: O=CCCCCCCOC1CCCCO1
Agent: C1=C(N2CCOCC2)CCC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1CCC=C1CCCCCCCO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-tetrahydropyranyloxy)heptanal (22 g.) and 1-morpholinocyclopentene, i.e. the morpholine enamine of cyclopentanone, (21.4 g.) in benzene (25 ml.) was heated under reflux for 12 hours under nitrogen, and the water liberated was continuously removed with a Dean and Stark head. Benzene (10 ml.) and then, dropwise, 18% hydrochloric acid (28 ml.) were added and the mixture was stirred for 2 hours. The organic layer was separated and evaporated. Concentrated hydrochloric acid (72 ml.) and butanol (300 ml.) were added to the residue. The mixture was heated at 100° C. for 1 hour, and then the solution was concentrated to give an oil. Diethyl ether was added, and the ether solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (11.7 g.), b.p. 125°-170° C/0.15 mm.Hg, nD25 1.490, μmax 228mμ (ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:16]([O:18]C)=[O:17])=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(C(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(C(=O)O)c1ccc(OCc2ccccc2)c(C)c1
Yield: 91.2 %

Procedure:
To a solution of compound 18 (220 mg, 0.674 mmol) in 5 ml of MeOH was added 5 ml of 20% NaOH solution in water and refluxed for 48 h. Reaction mixture is acidified to pH 1 with 1 M HCl solution and extracted with EtOAc (3×5 ml), the combined organic layers were washed with H2O and dried with Na2SO4. The solution was concentrated in vacuo to give compound 19 192 mg in 91% yield. Rf=0.10 (20% EtOAc/Hexane);
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1>CO.O1CCOCC1.[Ni]>[NH2:44][CH2:43][C:39]1[CH:38]=[C:37]([C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[O:29][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[S:16][N:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[C:5]([F:28])[CH:4]=2)[CH:42]=[CH:41][N:40]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3-c3ccnc(C#N)c3)cc2F)c(OC)c1
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: NCc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2Cl)ccn1
Yield: 10 %

Procedure:
5-chloro-4-[4-chloro-2-(2-cyanopyridin-4-yl)phenoxy]-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 340, 0.04 g, 0.00006 mol) was partially dissolved in methanol (5.0 mL) and 1,4-dioxane (5.0 mL). The solution was passed through an H-Cube™ at 70° C. with Raney nickel catalyst (30 mm cartridge) 3 times eluting with methanol to get complete conversion. Concentration in vacuo afforded the title compound as a colourless solid, 0.004 g, 10% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][O:13][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26]
Reactant: CCN(CCO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCOS(C)(=O)=O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester, methanesulfonyl chloride and triethylamine in methylene chloride was stirred at rt until all starting material were consumed. The mixture was quenched with water, brine and extracted with methylene chloride. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 6.83(s,2H), 6.25(s,1H), 4.34(t,2H), 3.86(s,3H), 3.6(t,2H), 3.38(t,2H), 3.09s,3H), 2.25(s,3H), 2.20(s,3H), 2.04(s,6H), 1.18(t,3H) ppm.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: CCSc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a mixture of 2-ethylsulfanylbenzoic acid (9.11 g), chloroform (100 ml), and oxalyl chloride (9.72 g), DMF (2 drops) was added, and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give 10.03 g of 2-ethylsulfanylbenzoic acid chloride (Compound (1H)-241).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH2:12][N:13]([CH3:15])[CH3:14])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH2:12][N:13]([CH3:14])[CH3:15]
Reactant: CN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN(C)CC(=O)Nc1ccccc1N
Yield: 77.8 %

Procedure:
N-(2-nitrophenyl)-2-dimethylaminoacetamide (13.8 g), platinum oxide (0.2 g) and ethanol (100 ml) were mixed together and shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until absorption of hydrogen ceased (4.5 litres of hydrogen were absorbed in 2hours). The mixture was then filtered and the ethanol evaporated off under reduced pressure. The solid residue so obtained was recrystallised from cyclohexane to give N-(2-aminophenyl)-2-dimethylaminoacetamide (9.3 g), m.p. 121°-123° C.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:20])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Oc1cccc2c1CCCC2
Product: CC(C)(C)NCC(O)COc1cccc2c1CCCC2

Procedure:
1-(tert.-butyl)-3-azetidinol and 5,6,7,8-tetrahydro-α-naphthol were reacted in the same manner as in Example 1 to form 1-(5,6,7,8-tetrahydro-α-naphthoxy)-3-(tert.-butylamino)-2-propanol. A hydrochloric acid gas was blown into the obtained propanol. As a result 1-(5,6,7,8-tetrahydro-1-naphthoxy)-3-(tert.-butylamino)-2-propanol hydrochloride having a melting point of 148°-150° C was obtained. The yield was 70%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=O)=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:25])[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:7]=1[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:2][CH2:3][CH3:4].Cl.C[N:41](C)CCCN=C=N.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][C:7]1[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:9](=[O:25])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][C:18]([C:22]([NH2:41])=[O:24])=[C:19]([CH3:21])[N:20]=1)=[CH:12][CH:11]=2)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Yield: 97.2 %

Procedure:
A solution of 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.60 g, 1.1 mmol), 1-ethyl,-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.42 g, 2.2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.33 g, 2.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl{6-[5-(-aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.58 g, 96.7%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](SC)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20].ClC1C=C(C=CC=1)C(OO)=O.[CH:32]([NH2:35])([CH3:34])[CH3:33]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:35][CH:32]([CH3:34])[CH3:33])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20]
Reactant: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Reactant: CC(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 8-bromo-2-(methylthio)-3-(pyridin-2-yl)quinazolin-4(3H)-one (179 mg, 0.514 mmol, 415c) in DCM (5.1 mL) was set stirring and 3-chloroperoxybenzoic acid (127 mg, 0.565 mmol, 77% max.; Sigma Aldrich) was added. The mixture was stirred for 4 h to give a mixture of sulfone and sulfoxide. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow residue. The residue and isopropylamine (1.7 mL, 19.73 mmol) was set stirring at 80° C. for 30 min. The reaction was cooled to RT and diluted with water. The mixture was extracted with DCM and dried over Na2SO4. Silica was added, and the material was adsorbed under reduced pressure. It was purified on 12 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give 8-bromo-2-(isopropylamino)-3-(pyridin-2-yl)quinazolin-4(3H)-one (71 mg, 30% for 2 steps). 1H NMR (400 MHz, DMSO-d6) ppm 8.69 (1H, dd, J=4.79, 1.08 Hz) 8.08 (1H, td, J=7.73, 1.76 Hz) 7.97 (1H, dd, J=7.63, 1.37 Hz) 7.88 (1H, dd, J=7.92, 1.47 Hz) 7.55-7.63 (2H, m) 7.03 (1H, t, J=7.73 Hz) 5.90 (1H, d, J=7.63 Hz) 1.15 (6H, d, J=6.65 Hz). m/z (ESI, +ve) 360.8 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[C:19]1([C:25](=[N:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:44]=2)[C:38](N(OC)C)=[O:39])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:25](=[N:32][C:33]2[CH:44]=[C:37]([C:38]([C:2]3[C:10]4[CH:9]=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=3)=[O:39])[CH:36]=[N:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Product: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (Preparation 101) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow oil in 32% yield, 460 mg.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O.[S]>>[OH:23][C:7]1[C:8]2[C:9](=[O:22])[C:10]3[C:15](=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=[CH:12][CH:11]=3)[C:16](=[O:18])[C:17]=2[C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Product: Nc1ccc(O)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
100 parts of 1,8-dinitroanthraquinone are added to a reaction mixture prepared from 1,000 parts of 20% strength oleum and 25 parts of boric acid. 15 parts of sulphur are then added at room temperature in the course of 25 minutes, and the reaction mixture is warmed to 60° C. and maintained at this temperature with stirring for 4 hours. After cooling down, the reaction product is precipitated out by the dropwise addition of 158 parts of 78% strength sulphuric acid and 500 parts of water, in each case with cooling, and isolated as indicated in Example 1. 61.6 parts of 1-hydroxy-4-amino-5-nitroanthraquinone are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][OH:28])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9].Cl[C:32]1C(C)=N[O:35][C:36]=1NS(C1C=CSC=1C(NC1C(C)=CC(C)=C(C(OC)=O)C=1C)=O)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][O:28][C:36](=[O:35])[CH3:32])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9]
Reactant: COC(=O)c1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Reactant: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1CO
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4, 6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].[F-].[Cs+]>O1CCOCC1>[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: Nc1cccc(Br)c1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2cccc(N)c2)cc1
Temperature: 120 °C

Procedure:
A sample of 3-bromoaniline (2.00 g, 11.6 mmol), 4-butylphenylboronic acid (3.1 g, 17.4 mmol) and cesium fluoride (5.3 g, 35 mmol) are charged to a microwave reaction vial and treated with anhydrous dioxane (12 mL) and bis(tri-tert-butylphospine) (600 mg, 1.16 mmol). The vial is sealed and purged with nitrogen for 5 minutes. The reaction is then heated to 120° C. for 5 minutes and filtered over celite washing with ethyl acetate. The solvent was removed and the crude material was purified by UV triggered reverse phase HPLC to afford the title compound: ESMS m/z 226.2 (M+H+).