Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH2:27])=[N:8][N:9]([C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:14]=4[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O>[NH2:27][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][N:9]([C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:14]=4[C:13]=3[N:12]=2)[N:8]=1
Reactant: CCOC(=O)c1cn(-c2ncc3c(n2)-c2ccc(OC)cc2CC3)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Temperature: 100 °C
Yield: 103.8 %

Procedure:
A mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester(3, 3.15 g, 8.63 mM), 1 N NaOH (15 mL), and methanol (20 mL) was heated at 100° C. for 3 hr then cooled to room temperature and diluted with water (100 mL). the pH was adjusted with 1 N HCl to approximately 3-4 and the resulting precipitate was isolated via filtration, washed with water (2×80 mL) and dried in vaccuo to give 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (4, 3.02 g, 100% yield). ES-MS MH+ 338.4 1H NMR (300 MHz, ppm, DMSO-d6): 8.81 (s, 1H), 8.57 (s, 1H), 8.2 (d, 1H), 7.0 (dd, 1H), 6.95 (s, 1H), 3.85 (s, 3H), 2.93 (m, 4H).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH:29]C=O)[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.CO>O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 86.5 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.6 g), conc.hydrochloric acid (1.1 g), methanol (20 ml) and tetrahydrofuran (15 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 3.0 with hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.3 g). mp. 201° to 213° C. (dec.).
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[CH:52]=[C:53]([OH:62])[CH:54]=[CH:55][C:56]=1[C:57]1[CH:61]=[CH:60][O:59][CH:58]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:52]=[C:53]([OH:62])[CH:54]=[CH:55][C:56]=1[C:57]1[CH:61]=[CH:60][O:59][CH:58]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: NCc1cc(O)ccc1-c1ccoc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)ccc1-c1ccoc1)C(=O)NC2=O
Yield: 50 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (˜15 mg, 0.058 mmol) and 3-Aminomethyl-4-furan-3-yl-phenol (40 mg, 0.21 mmol) in 50% yield: MS (ESI): 415.1 (M−1)−1.
Reaction SMILES: [CH:1]([C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:8][N:7]1[CH3:27])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C(O)(=O)C(C(C(O)=O)O)O.N>C(OCC)(=O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:8][N:7]1[CH3:27]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Agent: Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(CO)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Under argon, a solution of 244 mg (0.67 mmol) of 3-(9,10-didehydro-2-formyl-6-methyl-8α-ergolinyl)-1,1-diethylurea in 25 ml of absolute, freshly distilled tetrahydrofuran is added dropwise to a suspension of 52 mg (1.45 mmol) of lithium aluminum hydride in 3 ml of absolute, freshly distilled tetrahydrofuran at room temperature. The mixture is stirred for one hour at room temperature. The batch is cooled in an ice bath and combined in succession with 3 ml of 1N hydrochloric acid and 3 ml of 2N tartaric acid. The mixture is layered over with ethyl acetate and made alkaline with 12 ml of 1N ammonia solution. The ethyl acetate phase is separated and the aqueous phase is additionally extracted twice with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and concentrated. The product is crystallized from ethyl acetate, yielding 161 mg of 3-(9,10-didehydro-2-hydroxymethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (65% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(Br)cc2)N1
Solvent: C1CCOC1
Solvent: CSC
Product: Brc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine-2,5-dione (0.5 g, 1.34 mmol) in THF (10 mL) was added 2M B3.SMe2 (2.68 mL, 5.36 mmol). The mixture was stirred in RT under argon for 4 days; more 2M B3.SMe2 (2.68 mL, 5.36 mmol) was added and stirred for 3 days. Reaction mixture was quenched with EtOH (3 mL) and removed the solvent in rotavap, added EtOH (5 mL) and stirred at 70° C. for 2 hr and concentrated to give colorless oil as a crude product. MS (ESI) 345 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([CH:17]=[C:18]([CH2:27][CH3:28])[C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1.[OH-].[K+].CO.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([CH:17]=[C:18]([CH2:27][CH3:28])[C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2cc(CC)c(=O)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)O)cc2Cl)ccc2cc(CC)c(=O)oc12
Temperature: 30 °C

Procedure:
To a solution of methyl 3-chloro-4-(3-ethyl-8-propyl-7-coumarinoxy)propylthio)phenylacetate (Example 3; 30 mg, 0.0613 mmol) 1.0 mL methanol:water (2:1) was added a 0.5M solution of potassium hydroxide in methanol (0.61 mL, 0.3061 mmol). The mixture was heated to 30° C. for two hours at which time the mixture was acidified to pH=3 with 1M hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, and the crude residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane/1% acetic acid) which provided the title compound
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.[CH3:70][O:71][CH2:72]CN>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:70][O:71][CH3:72])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: COCCN
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: COCCNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 40 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 2-aminoethyl methyl ether (1.531 mmol, 133 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-methoxyethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96g (13 mg, 40%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.24 (s, 3H), 3.30 (s, 3H), 3.54 (m, 4H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.76 (m, 1H), 7.83 (m, 1H), 7.94 (m, 1H), 7.96 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H), 8.25 (s, 1H), 10.09 (s, 1H), 10.34 (s, 1H). (m/z)=530 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:41][CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COCCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-methoxyethylamine according to conditions described in general procedure C. Mp: 95-97° C.; 1H NMR (400 MHz, CDCl3) δ 3.25 (t, J=4.7 Hz, 4 H), 3.29 (s, 3 H), 3.43 (bs, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 5.32 (s, 1 H), 6.10 (s, 1 H), 6.77 (d, J=12.3 Hz, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 7.28-7.32 (m, 2 H), 7.50-7.59 (m, 2 H), 7.89-7.98 (m, 3 H), 8.13 (s, 2 H).
Reaction SMILES: O=[CH:2][CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][CH3:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][CH3:43])[CH2:2][CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CCNCCO[Si](C)(C)C(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reaction time: 11.5 h
Yield: 61.7 %

Procedure:
To a solution of (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 3.98 g, 8.25 mmol) and 2-(tert-butyldimethylsilyloxy)-N-ethylethanamine (INTERMEDIATE 63, 1.68 g, 8.25 mmol) in 1,2-dichloroethane (27.5 ml) was added sodium triacetoxyborohydride (2.62 g, 12.37 mmol). The resulting mixture was stirred in the dark for 11.5 h and was then quenched with 0.5 M aqueous sodium hydroxide (50 ml). After vigorous stirring for 10 min, the opaque mixture became clear. The layers were diluted with ethyl acetate and then separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride before being dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ISCO, 330 g SiO2, 50→100% ethyl acetate in hexanes for 20 mins then 0→20% methanol in ethyl acetate for 20 mins followed by 0→20% methanol in ethyl acetate over 20 min) to afford the title product (3.41 g, yield: 62%).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13](=[O:42])[C@H:14]([CH2:37][C:38]([F:41])([CH3:40])[CH3:39])[NH:15][C@@H:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[C:17]([F:20])([F:19])[F:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].O.[CH3:44][N:45](C=O)C>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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:1]([C@@H:3]([NH:12][C:13](=[O:42])[C@@H:14]([NH:15][C@@H:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[C:17]([F:20])([F:19])[F:18])[CH2:37][C:38]([F:41])([CH3:40])[CH3:39])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:44]#[N:45])=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1
Temperature: 90 °C

Procedure:
To N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide (1 eq) in DMF (0.1 M) were added Pd2(dba)3 (0.05 eq), dppf (0.05 eq), water (10 eq) and zinc cyanide (2.5 eq). N2 was bubbled into the mixture for 5 minutes and the mixture was then heated to 90° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc and saturated aqueous ammonium chloride, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and water, filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2]C.[Cl:15]C1C=C2C(=CC=1)NC(=O)C2=O.C(Br)C>>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH3:2])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CCBr
Product: CCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione using commercially available 5-chloro isatin and ethyl bromide, both purchased from Fisher Scientific. 1H NMR δ 7.58 (m, 2H), 6.88 (d, 1H), 3.80 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:38]=[C:29]1[C:30]2[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:33])[N:28]1[O:26][CH:23]1[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 2.5 ml, 5.5 mmol) was added to the mixture of N-Boc-4-hydroxypiperidine (1.0 g, 5.0 mmol), N-hydroxyphthalimide (816 mg, 5.0 mmol) and triphenylphosphine (1.3 g, 5.0 mmol) in THF (10 ml) at 0° C. and stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 30/70-70/30) to give tert-butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (1.37 g, 80%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])=[C:4]([CH3:27])[CH:3]=1.Cl.O>C(O)C>[OH:17][CH2:16][CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]1[CH:20]=[C:21]([F:26])[C:22]([F:25])=[C:23]([F:24])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:27]
Reactant: C=COCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCO)cc(F)c(F)c1F
Yield: 74.7 %

Procedure:
A solution of 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-N-(2-vinyloxyethoxy)-benzamide (3.00 g, 6.09 mmol) in ethanol (80 mL) was treated with 1 M aqueous hydrochloric acid (16 mL, 16 mol). The resultant solution was stirred for 2.5 h at ambient temperature. Water (50 mL) was added and the slurry was filtered. The solids were washed with ethanol-water (1:1, 150 mL) and recrystallized from methanol-acetone to afford N-(2-hydroxyethoxy)-2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-benzamide (2.12 g, 75%): m.p. 205-207° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1 H), 8.13 (s, 1 H), 7.54 (dd, J=8.9, 8.7 Hz, 1 H), 7.47 (d, J=1.0 Hz, 1 H), 7.32 9d, J=8.5 Hz, 1 H), 6.41 (dd, J=8.1, 5.0 Hz, 1 H), 4.69 (br s, 1 H), 3.79 (br s, 2 H), 3.52 (br s, 2 H), 2.20 (s, 3 H); MS (APCI+)=467.1; MS (APCI−)=465.1; Anal. Calcd/found for C16H14F3IN2O3: C, 41.22/41.28; H, 3.03/2.91; N, 6.01/5.79.
Reaction SMILES: C(OC1C=C([NH:15][C:16](N)=[S:17])C=CC=1)C1C=CC=CC=1.[O:19]([C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH2:31][NH:32][C:16]([NH2:15])=[S:17])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: NC(=S)Nc1cccc(OCc2ccccc2)c1
Product: NC(=S)NCCc1ccc(Oc2ccccc2)cc1

Procedure:
This compound is prepared via a method analogous to the method for preparation of N-(3-benzyloxyphenyl)thiourea using 4-phenoxyphenethylamine as the starting material. 1H NMR (CDCl3, δ): 2.92 (t, J=6.9 Hz, 2H), 3.31-3.90 (m, 2H), 5.65 (s, 2H), 5.85-6.16 (m, 1H), 6.97-7.04 (m, 4H), 7.11-7.15 (m, 1H), 7.19 (d, J=7.4 Hz, 2H), 7.36 (t, J=7.8 Hz, 2H); LCMS (M+1): 273
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23](OC)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[OH:24][CH2:23][C@H:11]1[C@@H:10]([NH:9][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12]1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of (3R,4S)-1-tert-butyl 3-methyl 4-((S)-1-phenylethylamino)piperidine-1,3-dicarboxylate (47 g, 0.13 mol, see Ko, S. S. et al., WO 2002/002525 for preparation of the enantiomer of this compound) in anhydrous ether (500 mL) at 0° C. was added 1M-LAH (100 mL, 0.1 mol) dropwise, and the mixture was stirred at 015° C. for 3 h. The reaction was quenched with a portion-wise addition of Na2SO4.10H2O (excess) and stirring for 1 h at rt. It was filtered through Celite and the solvent was evaporated off to give (3R,4S)-tert-butyl 3-(hydroxymethyl)-4-((S)-1-phenylethylamino)piperidine-1-carboxylate (quantitative yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (198 mg, 1.21 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21 mmol, 1.0 eq) in 1,2-dichloroethane (8 mL) and methanol (2 mL), followed by acetic acid (80 μL, 1.39 mmol, 1.15 eq) and sodium cyanoborohydride (99 mg, 1.57 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester as an orange oil (359 mg, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH3:25])=[CH:18][C:3]=1[N:4]([CH2:15][CH2:16][OH:17])S(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O.N>O>[NH2:1][C:2]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH3:25])=[CH:18][C:3]=1[NH:4][CH2:15][CH2:16][OH:17]
Reactant: Cc1ccc(S(=O)(=O)N(CCO)c2cc(C)cc([N+](=O)[O-])c2N)cc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(NCCO)c(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
0.0458 mol (16.7 g) of 2-amino-3-nitro-5-methyl-N-(β-hydroxyethyl)-N-tosylaniline is introduced, whilst stirring, into 167 ml of concentrated sulphuric acid to which 48 ml of water has been added. The mixture is heated for 1 hour on a boiling water-bath and then poured onto 850 g of crushed ice. The sulphuric acid solution is neutralised with the aid of ammonia solution. The expected product precipitates. After filtration, washing with water, drying in vacuo and recrystallisation from ethanol, it melts at 166° C.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[C:27]([O:29]CC2C=CC=CC=2)[C:26]([CH:37]([CH3:39])[CH3:38])=[CH:25][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=2)[CH2:14]1)=[O:12])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>CN(C=O)C>[C:57]([O:56][C:54]([N:61]1[CH2:62][CH2:63][N:64]([C:22]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:11](=[O:12])[C:10]2[CH:25]=[C:26]([CH:37]([CH3:39])[CH3:38])[C:27]([OH:29])=[CH:28][C:9]=2[OH:8])[CH2:21]3)=[O:23])[CH2:65][CH2:66]1)=[O:55])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3C2)c(O)cc1O
Yield: 102.2 %

Procedure:
A solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (Preparation D6) (0.5 g, 0.96 mmol), EDC (0.22 g, 1.15 mmol), HOBT (0.196 g, 1.15 mmol) and BOC piperazine (0.117 ml, 1.06 mmol) in DMF (10 ml) was stirred at room temperature for 48 hours, then evaporated under vacuum. The crude material was dissolved in ethyl acetate and extracted twice with saturated NaHCO3, organics washed with brine, dried (MgSO4), filtered then evaporated under vacuum and purified by flash column chromatography (80% EtOAc-P.E. as eluant) to give 0.5 g of 4-[2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester. MS: [M+H]+ 688.