Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:23]1([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]3[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=3)[CH:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COC(OC)c1cc(Oc2cccc(NC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.0125 mol) was dissolved in DCE (150 mL), and cyclohexanone (0.0125 mol) was added, followed by NaBH(OAc)3 (0.0187 mol). The reaction mixture was stirred overnight at room temperature. Some extra NaBH(OAc)3 was added, and the reaction mixture was stirred overnight at room temperature. A 10% NaOH solution (150 mL) was added, and this mixture was extracted with diisopropyl ether. The separated organic layer was dried (MgSO4) and filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 20:80 up to 5:95 hexane:CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:24][C:25](Cl)=[O:26].[OH-].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([CH3:13])[CH2:11][O:12][CH2:24][C:25]2=[O:26])=[CH:14][CH:15]=1
Reactant: COc1ccc(CNCC(C)CO)cc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CC(C)COCC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 3-(4-methoxy-benzylamino)-2-methyl-propan-1-ol (4.14 g, 19.8 mmol) in dichloromethane (60 ml) was added triethylamine (2.20 g, 21.8 mmol) and chloroacetyl chloride (2.46 g, 21.8 mmol) at 0° C. The mixture was stirred at 0° C. for one hour and partitioned between 0.5N—HCl and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (66.7 ml), then potassium hydroxide (2.22 g, 39.6 mmol) was added at 0° C. The mixture was stirred for 16 hours and partitioned between saturated ammonium chloride aqueous solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=1/1 to 1/3) to afford 4-(4-methoxy-benzyl)-6-methyl-[1,4]oxazepan-3-one as white solid (4.35 g, 88%).
Reaction SMILES: C([Mg]Br)(C)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1.[CH2:15]([Si:19](Cl)([CH3:21])[CH3:20])[CH2:16][CH2:17][CH3:18]>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH3:21])[CH3:20])=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: CCCC[Si](C)(C)Cl
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CCCC[Si](C)(C)C#Cc1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
i-propylmagnesiumbromide (0.67 M/THF solution, 3.10 mL, 2.1 mmol) was added dropwise to THF solution (15 mL) of 1-bromo-4-ethynylbenzene (382 mg, 2.0 mmol) at 0° C. After the mixture was stirred for 20 minutes, an ice water bath was removed. After stirring at room temperature for 10 minutes, n-butyldimethylsilyl chloride (0.69 mL, 4.0 mmol) was added to the mixture. After stirring for 2 hours, the reaction was terminated by the addition of saturated ammonium chloride solution (5 mL). The reaction mixture was extracted with ethyl acetate, and it was concentrated and thereafter purified by means of flash column chromatography to obtain (4-bromophenylethynyl)-n-butyldimethylsilane (530 mg, isolated yield: 90%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:21])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].Cl.CS(O)(=O)=O.[CH2:28](O)[CH2:29][OH:30]>>[CH3:1][N:2]1[CH2:3][CH2:4][C@@:5]23[C:6]4[C:7]5[CH2:20][C@@H:19]1[C@@H:18]2[CH2:17][CH2:16][C:14]1([C@@H:13]3[O:12][C:11]=4[C:10]([OH:21])=[CH:9][CH:8]=5)[O:30][CH2:29][CH2:28][O:15]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Reactant: OCCO
Agent: CS(=O)(=O)O
Agent: Cl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 80 °C
Yield: 99.9 %

Procedure:
To Hydromorphone HCl (15.0 g, 46.7 mmol) was added ethylene glycol (80 mL) and methane sulfonic acid (10 mL) and the reaction heated at 80° C. overnight. The reaction was cooled to room temperature and poured into ice/NH3(aq) (˜350 mL). The product was extracted with dichloromethane and dried over MgSO4 before concentration under reduced pressure to give (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-ol (19 g, 99.9% LCMS); [M+H]+ 330.5. This was taken onto the next step without purification.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[CH:21][C:22]([OH:36])=[C:23]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Br)[CH:38]=[CH2:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:39]([O:36][C:22]1[CH:21]=[CH:20][C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][C:23]=1[N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH:38]=[CH2:37]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](Oc1ccc(O)c(N2C(=O)c3ccccc3C2=O)c1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N1C(=O)c2ccccc2C1=O
Yield: 88.9 %

Procedure:
A mixture of Example 73C (7 g, 14.2 mmol), allyl bromide (1.84 mL, 21.27 mmol) and K2CO3 (3.92 g, 28.36 mmol) in anhydrous acetone (200 mL) were stirred, and refluxed overnight. The suspension was filtered, and dried with silica gel powder (20 g). 15% ethyl acetate in hexanes (2 L) was used to run flash chromatography to give the title compound (6.74 g, 89%). MS (DCI) m/z 551.13 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 9H) 4.37–4.43 (m, 2 H) 5.02–5.22 (m, 2 H) 5.83 (m, 1 H) 6.65–6.69 (m, 2 H) 6.83 (d, J=2.37 Hz, 1 H) 7.34–7.47 (m, 6 H) 7.70–7.78 (m, 6 H) 7.89–7.94 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6](SC#N)[N:5]2[N:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:5]2[N:18]=1
Reactant: Cc1nc2n(n1)C(SC#N)=Nc1ccccc1C2
Reactant: CN1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1nc2n(n1)C(N1CCN(C)CC1)=Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.25 g of 2-methyl-5-cyanothio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine in 7.3 ml of hexamethylphosphoramide is added dropwise, at 0°, 4.94 g of N-methylpiperazine over a period of 5 minutes. The mixture is stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and evaporated to dryness to give 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine, m.p. 185°-187°. This material is treated with an equivalent amount of maleic acid to give 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine monomaleate of example 1.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[S:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CS(C)=O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:5]3[S:4][N:3]=[C:2]([NH:23][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)[N:6]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: Clc1nsc(-c2ccc3[nH]ccc3c2)n1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2nsc(-c3ccc4[nH]ccc4c3)n2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A mixture of 3-chloro-5-(1H-indol-5-yl)-1,2,4-thiadiazole (0.67 g, 2.85 mmol) and 4-methoxybenzylamine (1.95 g, 14.25 mmol, Aldrich) in DMSO (7 mL) was stirred for 12 h at 110° C. The reaction was cooled to RT and quenched with ice cold water (50 mL) and extracted into EtOAc (20 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by using silica-gel column chromatography (eluent: 30-40% EtOAc and petroleum ether) to give 5-(1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (670 mg, 70.5%) as a off brown solid. MS (ESI, pos. ion) m/z: 337.1 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.44 (brs, 1H), 8.21 (d, J=9 Hz, 1H), 7.73 (dd, J=8.4, 1.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.28-7.26 (m, 1H), 6.90 (dd, J=6.9, 2.1 Hz, 2H), 6.64 (m, 1H), 5.42 (m, 1H), 4.62 (d, J=7.6 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1([CH2:29][CH:30]=[CH2:31])[N:13]2[CH2:14][CH2:15][C:16]3[C:21]([C:12]2=[CH:11][C:10]2[CH:9]=[CH:8][C:7]([O:25][CH3:26])=[C:6]([O:27][CH3:28])[C:5]1=2)=[CH:20][C:19]1[O:22][CH2:23][O:24][C:18]=1[CH:17]=3)[CH:2]=[CH2:3].[BH4-].[Na+]>CO>[CH2:29]([C:4]1([CH2:1][CH:2]=[CH2:3])[N:13]2[CH2:14][CH2:15][C:16]3[C:21]([CH:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:25][CH3:26])=[C:6]([O:27][CH3:28])[C:5]1=2)=[CH:20][C:19]1[O:22][CH2:23][O:24][C:18]=1[CH:17]=3)[CH:30]=[CH2:31]
Reactant: C=CCC1(CC=C)c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCC1(CC=C)c2c(ccc(OC)c2OC)CC2c3cc4c(cc3CCN21)OCO4
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64177 %

Procedure:
To a solution of 8,8-diallyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (110 mg, 0.26 mmol) in methanol (20 mL) was added sodium borohydride (10 mg, 0.26 mmol) in small portions at 25° C. After stirring at 25° C. for 20 min, the mixture was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 8,8-diallyl-9,10-dimethoxy-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (70 g, 64%). LC/MS m/e calcd for C26H29NO4 (M+H)+: 420.53, observed: 420.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.44 (m, 2 H) 2.54-2.64 (m, 1 H) 2.64-2.75 (m, 3 H) 2.90 (s, 2 H) 3.02-3.12 (m, 2 H) 3.80 (d, J=2.78 Hz, 6 H) 4.30 (d, J=2.02 Hz, 1 H) 4.69 (d, J=10.36 Hz, 1 H) 4.74-4.88 (m, 2 H) 5.01 (d, J=16.93 Hz, 1 H) 5.36-5.48 (m, 1 H) 5.58-5.72 (m, 1 H) 5.93 (s, 2 H) 6.63 (s, 1 H) 6.78-6.85 (m, 2 H) 6.94 (d, J=8.59 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[N:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:28]([C:25]1[N:24]=[CH:23][C:22]([NH:21][C:18]([C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:19])=[CH:27][CH:26]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (S)—N-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (0.666 g, 2.40 mmol) and 3-amino-6-pentylpyridine (0.330 g, 2.01 mmol) in chloroform (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.460 g, 2.40 mmol) and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was allowed to proceed overnight and then partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a faint green foam.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([CH3:16])[C:4]1=[O:17])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([CH3:16])[C:4]1=[O:17])[CH3:2]
Reactant: CCn1c(=O)c(C)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccccc1
Product: CCn1c(=O)c(C)cc2cnc(Nc3ccccc3)nc21
Temperature: 175 °C
Yield: 15 %

Procedure:
A mixture of 8-ethyl-6-methyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (123 mg, 0.49 mmol) and 1 mL of aniline was heated at 175° C. for 20 minutes. The reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Hexane was added to the residue, and the resultant solid was collected by filtration and purified by flash chromatography eluting with ethyl acetate to provide 21 mg (15%) of 8-ethyl-6-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 178-180° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2c(C)cc(C)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 60 °C
Yield: 16 %

Procedure:
Combine 1-iodo-2,4,6-trimethylbenzene (2.966 g, 12.05 mmol), 4-carboxyphenylboronic acid (1.0 g, 6.026 mmol), Pd(OAc)2 (0.0067 g, 0.005 mmol), tetrabutylammonium bromide (0.388 g, 1.206 mmol), and potassium phosphate (2.557 g, 12.05 mmol). Purge the reaction vessel with argon and add anhydrous DMF (20 mL) to the reaction mixture. Heat the sealed reaction vessel to 120° C. with stirring until completion as determined by TLC. Cool reaction mixture to room temperature. Add methyl iodide (1.0 mL, 36.63 mmol) to reaction mixture with continued stirring until completion. Dilute the reaction with ethyl acetate and filter though a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 2′,4′,6′-trimethylbiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (45 mL) and water (5 mL) containing 5 eq of LiOH with stirring at 60° C. Upon completion, evaporate the solvent, acidify the reaction mixture with hydrochloric acid, and extract with ethyl acetate. Dry the organics over MgSO4, filter, and evaporate to yield 0.023 g (16%) of the title compound. MS (ES): m/z 239.1 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]=2[CH:27]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:32].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[C:17]([NH:16][C@H:9]1[C:8]2[CH:27]=[C:4]([C:1](=[O:3])[CH2:2][OH:32])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]1[OH:15])=[O:26]
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc(F)c(Cl)c1)[C@H](O)C(C)(C)O2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2ccc(F)c(Cl)c2)[C@@H]1O
Yield: 23.5 %

Procedure:
(3S,4S)-6-Acetyl-4-(3-chloro-4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D4 (1.97 g, 5.0 mmol) (Example 17 of WO95/34545) was dissolved in acetonitrile (25 ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo giving a yellow solid which was isolated by filtration and recrystallised from ethyl acetate/hexane to give the title compound as a white solid (0.48 g, 24%), m.p. 200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N+:15]#[C-])[C:6]([CH3:14])([CH3:13])[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH2:15])[C:6]([CH3:14])([CH3:13])[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2]
Reactant: [C-]#[N+]C(C(=O)OCC)C(C)(C)C(=O)OCC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOC(=O)C(C)(C)C(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-Isocyano-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester (3.75 g, 15.5 mmol) is dissolved in methanol (100 mL) and the mixture is cooled to 0° C. with an ice bath. To this is added, dropwise, 37% aqueous hydrochloric acid (1.58 g). The reaction is stirred 20 minutes and neutralized with 1 M aqueous sodium hydroxide. The volatiles are removed under vacuum and then the product is extracted into ethyl acetate (2x) and washed with water (2x). The combined organic phases are dried over sodium sulfate and evaporated to give 3-amino-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:3]=1.Cl.O1CCOCC1>O>[CH3:43][N:40]1[CH2:41][CH2:42][N:37]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]5[CH:19]=[N:20][C:21]([N:24]6[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]6)=[N:22][CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)cc4C3)nc(N)n2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCNCC6)nc5)cc4C3)nc(N)n2)CC1

Procedure:
A mixture of tert-butyl 4-(5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-yl)piperazine-1-carboxylate (10 mg, 0.02 mmol, Example 8) and a solution of hydrogen chloride in 1,4-dioxane (0.01704 mL, 0.06817 mmol, 4 M) with a few drops of water was stirred at r.t. for 2 hours. The solution was concentrated. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=487.4.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[NH2:7])[CH3:3].C(N(CC)CC)C.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[NH:7][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A stirred suspension of L-leucine ethyl ester hydrochloride (8.38 g, 45 mmol) in dry THF (80 ml) at room temperature was treated with triethylamine (6.3 ml, 45 mmol). The reaction mixture was treated with 6-bromohexanoyl chloride (6.91 ml, 45 mmol). The reaction mixture was stirred for 4 h at room temperature and then diluted with a mixture of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give N-6-bromohexanoyl-L-leucine ethyl ester (12.1 g, 80%) as an oil which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[N:9]2)=[CH:5][CH:4]=1.O[Li].O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nn1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of ethyl 1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (190.0 g, 0.73 mol) and MeOH/H2O (350 mL/100 mL) was added LiOH.H2O (42.0 g, 0.97 mol) in portions at 0° C. and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated, the residue was diluted with water (250 mL), then extracted with Et2O (3×75 mL) to remove neutral impurities. The aqueous layer was adjusted to pH=3-4 with conc. HCl and the precipitate was filtered to afford the title compound (160 g, 94.0%) as a white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:28]4[C:19](=[CH:20][C:21]5[O:26][CH2:25][CH2:24][O:23][C:22]=5[C:27]=4[F:29])[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:29][C:27]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:30])[C:28]=12
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: MS (ES+) m/z 313.8 (M+1).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)=[C:41]([S:53]([CH3:56])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)=[C:41]([S:53]([CH3:56])(=[O:55])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cccc(-c2ccc(Br)cc2S(C)(=O)=O)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COc1cccc(-c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)OC(C)(C)C)cc2S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-3′-methoxy-2-(methylsulfonyl)biphenyl (Intermediate 207), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.