Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCC1CCCO1
Product: O=[N+]([O-])c1cc(OCC2CCCO2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-tetrahydro-furan using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-tetrahydro-furan which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: Clc1ccc(-c2nc3n(c2Cl)CCCC3)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(-c2nc3n(c2Cl)CCCC3)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 1.1 g (3.85 mmol) sample of 3-chloro-2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine was added to 8.0 ml of a 1:1 mixture of concentrated sulfuric/nitric acid at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes followed by warming to 20° C. After pouring the reaction mixture onto ice/water, the resulting aqueous mixture was extracted with 400 ml of ethyl acetate. The separated organic layer was washed with water, brine, and dried over magnesium sulfate. The yellow oily solid residue obtained after evaporating in vacuo was flash chromatographed on silica gel (1:1 hexane/ethyl acetate) to provide 0.8 g of the title compound as a yellow solid (m.p. 111°-112° C.). NMR (CDCl3, 200 MHz): δ1.95 (m, 2H), 2.05 (m, 2H), 2.91 (t, 2H), 3.92 (t, 2H), 7.66 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [CH:1]1([CH:4]([NH:6][C:7]2[C:19]3[C:18]4[CH:17]=[C:16]([F:20])[CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:21]#[N:22])=[CH:9][N:8]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=[O:24].[K+].[K+].OO>CS(C)=O>[CH:1]1([CH:4]([NH:6][C:7]2[C:19]3[C:18]4[CH:17]=[C:16]([F:20])[CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:21]([NH2:22])=[O:24])=[CH:9][N:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12)C1CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Nc1ncc(C(N)=O)c2[nH]c3ccc(F)cc3c12)C1CC1
Temperature: 70 °C

Procedure:
1-[(1-Cyclopropylethyl)amino]-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (113.9 mg, 0.39 mmol) and K2CO3 (321 mg, 2.32 mmol) was dissolved in DMSO (1.8 ml). Hydrogen peroxide (30%, 0.30 ml, 3.10 mmol) was added and the solution was heated at 70° C. for 3 h. HPLC/MS then showed complete conversion. The solution was cooled to ambient temperature and directly purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CD3COCD3) δ11.14 (br s, 1H); 8.61 (s, 1H); 7.95 (dd, 1H); 7.77 (dd, 1H); 7.17 (dt, 1H); 6.16 (d, 1H); 4.10 (m, 1H); 1.42 (d, 3H); 1.26 (m, 1H); 0.52 (m, 1H); 0.45 (m, 2H); 0.31 (m, 1H). LRMS (APCI) calc'd for (C17H18FN4O) [M+H]+, 313.1. found 313.1.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23]C)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br>C(O)(=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: Br
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Temperature: 80 °C
Yield: 385.9 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (1.0 g, 2.97 mmol) in acetic acid (40 mL) was treated with 48% aqueous HBr (37.7 mL) and heated at 80° C. for 5 h before being concentrated in vacuo. The resultant residue was suspended in water (60 mL) and pH adjusted to ˜6 using 5N aqueous NaOH. The precipitate formed was filtered off, washed with water then dried in vacuo. The resultant solid was triturated in acetone to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol as a beige solid (3.58 g, 69%). LCMS RT=2.04 min, [M+H]+=313. 1H NMR 400 MHz (DMSO-d) δ: 8.42 (1H, s), 7.90 (1H, s), 7.83 (1H, s), 5.84 (1H, s), 5.78 (1H, m), 4.71-4.30 (4H, m), 1.45 (6H, d, J=6.60 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1.CO.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][N:12]([CH:25]2[CH2:27][CH2:26]2)[CH2:11]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CNCCO2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CN(C3CC3)CCO2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 244B (250 mg), anhydrous methanol (6 mL), (1-ethoxycyclopropoxy)trimethylsilane (0.474 mL), and acetic acid (0.509 mL) was heated at 70° C. for 30 minutes. After cooling to ambient temperature, sodium cyanoborohydride (112 mg) was added and the mixture was stirred for 18 hours. Additional sodium cyanoborohydride (75 mg) was added and stirring was continued 18 hours. The reaction was concentrated and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product was isolated from the dried methylene chloride layer and was purified on silica gel and was eluted with a 1, 2.5, 5, 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23]O>>[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([O:18][CH3:23])=[O:17])[C:14]=2[OH:22])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cc2ccccc2)c1O
Yield: 46 %

Procedure:
To a solution of the acid (0.47 g, 2.1 mmol) in dry methanol (40 ml) was added conc. Sulfuric acid (0.47 g) and the solution heated to reflux for 96 h. Upon cooling the methanol was removed and the residue taken up in water (50 ml), and extracted with dichloromethane (3×30 ml). The combined extracts were dried (Na2SO4), and the solvent removed. The residue was eluted through a silica column using 5% ethyl acetate in petroleum spirit to yield a colorless oil (0.23 g, 46%). 1H-NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 4.03 (s, 2H), 6.81 (t, 1H, J=8 Hz), 7.20-7.32 (m, 6H), 7.73 (dd 1H, J=8 Hz, 1.5 Hz), 11.10 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:34](=[O:38])[C:35](Cl)=[O:36])=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:35](=[O:36])[C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([O:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1Cl
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(C(C)(C)C)cc1NC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
5-tert-Butyl-3-chloro-2-methoxy-phenylamine (25) (77 mg, 0.36 mmol) was dissolved in 10 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.54 mmol), prepared as described before, and DIEA (0.37 mL, 1.44 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=524. Observed mass=525
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][S:7]1(=[O:10])=[O:11])#[N:20]
Reactant: COC(=O)C1CCS(=O)(=O)N1Cc1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (6.0 g, 20.4 mmol) in a tetrahydrofuran-water mixture (4:1, 50 mL), lithium hydroxide monohydrate (2.5 g, 59.6 mmol) was added at room temperature and stirred at this temperature for 4 h. Then tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residual reaction mixture was cooled to 0° C. and 1N hydrochloric acid was added to make the pH˜2. The acidified reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (2×50 mL) followed by brine (50 mL) and then dried over sodium sulfate and concentrated under reduced pressure to provide 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (5.2 g, 91%).
Reaction SMILES: [C:1]([Cl:5])(=O)OC.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH3:12][C:6]1[CH:11]=[CH:10][C:9]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:8][C:7]=1[CH2:1][Cl:5]
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
315 mg (1.40 mmol) of N,N-dimethyl-(2-methyl-5-phenylbenzyl)amine (produced in the same manner as in Intermediate Production Example 12) was dissolved in 3 ml of toluene, and to this solution was added 370 mg (3.92 mmol) of methyl chlorocarbonate at room temperature. Directly after addition, the reaction mixture tuned to white suspension. This while suspension was stirred at room temperature for 7 hours, then, washed with 1 N hydrochloric acid, saturated sodium bicarbonate water, and saturated saline, sequentially, and dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane, then, hexane/ethyl acetate=10/1 (v/v)), to obtain 282 mg of 2-methyl-5-phenylbenzyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[N:39]=[C:22]4[C:23]([C:27]5[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=5[O:37][CH3:38])=[CH:24][CH:25]=[CH:26][N:21]4[N:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:38][O:37][C:28]1[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:27]=1[C:23]1[C:22]2[N:21]([N:20]=[C:19]([NH:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)[N:39]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNC4)nc12

Procedure:
[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine was prepared from 6-[8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.255 g). MP=99-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.38 (m, 3H), 7.05 (t, 1H), 6.85 (d, 1H), 3.85 (s, 3H), 3.75 (s, 2H), 2.92 (m, 2H), 2.63 (br m, 3H): MS=440 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.28 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (148 mg, 0.56 mmol) and K2CO3 (115 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h, additional Pd (PPh3)4 (16 mg, 0.014 mmol) was added into the reaction mixture and stirring continued at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide as an off-white solid. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (m, 3H), 7.6 (d, 2H), 7.23 (s, 1H), 6.9 (d, 2H), 4.7 (m, 1H), 4.3 (m, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 2.8-3.1 (m, 7H), 2.6 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH2:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CCC=C2
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
4 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthalenol [J. Pharm. Soc., Jan, Vol. 64, (1944), p. 153], 53 ml of toluene and 180 mg of p-toluene sulfonic acid were mixed together and then stirred for 2 hours at 130° C. while distilling off ≃ 20 ml of solvent. Then, at 20° C. 50 ml of water were added and extraction was done with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium bicarbonate, and with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue was crystallized from ethanol to obtain 2.75 g of the expected product melting at ≃35° C. and after crystallizing from isopropanol melting at 37° C.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:33])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH3:33][S:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH:10]=1)(=[NH:6])=[O:8]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=N)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Yield: 77 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(thiazol-2-ylamino)quinazolin-7-yl]amino}methyl)phenyl]sulphoximide (40 mg, 0.083 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→20% methanol) gives the desired product in 77% yield (26 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:10]([OH:18])[C:11]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])=O)(C)(C)C.[ClH:26]>CO>[ClH:26].[NH2:8][C@@H:9]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:10]([OH:18])[C:11]([NH:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)CNC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)CNC(=O)C(O)[C@@H](N)CC1CCCCC1

Procedure:
To a solution of 590 mg of the amide compound in 10 ml of methyl alcohol was added 3.3 ml of a 2N-hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction mixture was evaporated under reduced pressure to obtain 254 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxy-N-isobutylbutyramide hydrochloride as a white powder.
Reaction SMILES: COC([C:5]1[N:6]([NH:14][C:15]([NH:17][C:18](=[O:25])C2C=CC=CC=2)=[S:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[OH-].[Na+].O.C(O)(=O)C>>[S:16]=[C:15]1[NH:17][C:18](=[O:25])[C:5]2=[CH:13][C:12]3[C:7]([N:6]2[NH:14]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(=O)c1cc2ccccc2n1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=S)[nH]n2c1cc1ccccc12
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Into a 1 L beaker, 1-(3-benzoyl-thioureido)-1H-indole-2-carboxylic acid methyl ester (24.27 g, 0.07 mol) and a 2 M solution of sodium hydroxide in water (140 mL, 0.28 mol) were added. The mixture was heated at 85° C. for 75 minutes. The reaction was cooled to room temperature. Acetic acid (16.7 mL, 0.29 mol) was added at 0° C. and the mixture was stirred for 30 minutes. The solid was filtered and dried on filter overnight to afford a white solid, which was further dried under vacuum overnight. NMR indicated about 1:1 molar ratio of product to benzoic acid. Trituration and filtration from hot benzene removed the benzoic acid and afforded 2-thioxo-2,3-dihydro-1H-[1,2,4]triazino[1,6-a]indol-4-one (14.50 g, 96%), which was used in the next step without further purification. 1H-NMR (DMSO-d6) δ 10.29 (br s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.3 (br s, 1H), 7.27 (m, 1H), 7.12 (m, 1H), 6.88 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].[OH-].[K+]>O1CCCC1.CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (81.6 mg, 0.140 mmol) and 4-bromo-2-methyl-2-butanol (117 mg, 0.700 mmol) in tetrahydrofuran (1 ml) was added 1M KOH solution in methanol (1 ml), and the mixed solution was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was diluted with hexane, washed with brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to give the title compound as a colorless oil (60.3 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CCO.[Ni].O>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ncc2cc(-c3ccc(F)c(N)c3)c(=O)n(C)c2n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(-c2ccc(F)c(N)c2)cc2cncnc21
Yield: 46.8 %

Procedure:
A solution of Example A3 (2.5 g, 7.9 mmol) in EtOH (30 ml) was treated with Raney Nickel® (50% slurry in water, 10 g, 85 mmol) and the mixture was refluxed for 3 h. The cooled reaction was filtered and the filtrate was concentrated to give the crude product, which was washed with cold MeOH (2 mL) to give 6-(3-amino-4-fluoro-phenyl)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 47% yield). 1H NMR (300 MHz, DMSO-d6)δ 9.10 (s, H), 9.07 (s, 1 H), 8.06 (s, 1 H), 7.14 (dd, J=8.7, 2.1 Hz, 1 H), 7.05 (dd, J=11.4, 8.4 Hz, 1 H), 6.82 (m, 1 H), 5.22 (s, 2 H), 3.68 (s, 3 H); MS (ESI) m/z: 271.3 (M+H+).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16])=O)(C)(C)C.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(=O)NC1=O
Reaction time: 4 h

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit.276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7 (C-6′), 165.3 (C-2′), 165.2 (C-1 & C-3), 133.1 (C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C-4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.