Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.O[C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH3:16])[N:10]=1.[C:17](O)(=O)C>[OH-].[Na+]>[CH3:17][N:10]1[C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]([CH3:9])[C:7]1=[O:6]
Reactant: Cc1cc(O)nc(O)n1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)n(C)c(=O)n1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
(See, e.g., Azas et al., Farmaco. 58:1263-1270 (2003)). Dimethylsulfate (106 g, 80 ml, 844 mmol) was added dropwise to a solution of 2,4-dihydroxy-6-methylpyrimidine (30 g, 238 mmol) in 280 mL of 4 N NaOH at 40° C. After stirring for 4 h at 40° C., the reaction mixture was neutralized with careful addition of acetic acid and extracted 3 times with 100 mL of ethyl acetate. Combined organics were dried over MgSO4 and concentrated in vacuo to yield a white solid. Recrystallization from ethanol yielded 2 (15.8 g, 43%): mp 113-114° C.; 1H NMR (DMSO-d6): δ 5.58 (s, 1H), 3.26 (s, 3H), 3.09 (s, 3H,), 2.19 (s, 3H,); MS (ES+) (m/z): [M+1]+ calculated for C7H11N2O2, 155.17. found 155.93. This compound matched the analytical data as reported (see, e.g., Azas et al., Farmaco. 58:1263-1270 (2003)).
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[C:19]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:43]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])=[C:19]([N:33]([CH3:43])[S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(NS(=O)(=O)c3ccccc3)c2)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1NS(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeI (45 μL, 0.72 mmol) was added to a mixture of N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide (0.189 g, 0.36 mmol) and K2CO3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at r.t. for 2 h, filtered and the solvent was removed. Purification by column chromatography (DCM/MeOH/heptane 4:1:15) gave N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)-amino]phenyl}benzenesulfonamide as a colourless oil. Boc-deprotection was carried out by dissolving the compound in small amount of MeOH and adding HCl/ether. The solvent was removed and the residue was recrystrallized from MeOH/ether to give 62.7 mg of product M+1 501.3 Calcd 501.16.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: O=Cc1cccc(OCCBr)c1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCn2ncc3ccccc3c2=O)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A mixture of 3-(2-bromoethoxy)benzaldehyde (6.00 g), 1(2H)-phthalazinone (4.21 g), potassium carbonate (7.24 g) and N,N-dimethylformamide (40 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 3-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (6.94 g, yield 90%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 110–111° C.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[C:9]([O:17][C:18]([F:21])([F:20])[F:19])[CH:8]=2)[NH:3]1.CO.[ClH:24]>O1CCOCC1>[ClH:24].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[NH:3][C:2](=[O:1])[O:6][N:5]=2)=[CH:8][C:9]=1[O:17][C:18]([F:19])([F:21])[F:20]
Reactant: CC(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture consisting of 200 mg of N-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-2-trifluoromethoxyphenyl]acetamide, 10 ml of methanol and 0.5 ml of a 4M solution of hydrochloric acid in dioxane was stirred at room temperature for 15 hours. After concentrating the volatile fractions on a rotary evaporator, a yellowish oil remains.
Reaction SMILES: C([O:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11]
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(O)C=O)CC2)cc1
Yield: 75 %

Procedure:
A solution of N-(benzyloxy)-N-((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)formamide (100 mg, 0.22 mmol) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (10%, 23 mg, 0.02 mmol, 0.1 eq.) for 2 h at room temperature. The mixture was filtered on a bed of cellite, evaporated to give the title product as an orange foam (60 mg, 75%). HPLC, Rt: 1.95 min (purity: 100%). M+(LC-MS (ESI)): 364.4.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[O:33][CH2:34][CH2:35][CH3:36])=[O:25])[NH:21][C:22]=1[CH3:23].CCN(C(C)C)C(C)C.O>CN1CCCC1=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][N:30]([C:2]3[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)[N:6]=3)[CH2:29][C@@H:28]2[O:33][CH2:34][CH2:35][CH3:36])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: CCCO[C@@H]1CNCC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Reactant: COC(=O)c1sc(Cl)nc1-c1ncnn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Methyl 2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Intermediate 2, 68 mg, 0.267 mmol) was added to a solution of 4-chloro-5-methyl-N-[(3R,4S)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 74, 80 mg, 0.267 mmol) and DIPEA (0.04 mL, 0.8025 mmol) in N-methyl 2-pyrrolidinone (1.0 mL) and the resulting reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and poured into water (30 mL). The solid that formed was collected by filtration, washed well with diethyl ether (30 mL) and dried to afford methyl 2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate 80 mg (57.1%) as solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 325 %

Procedure:
A mixture of 6-bromo-2-quinolinecarboxylic acid (331 g, from multiple batches, 1.31 mol) and methanesulfonic acid (22 mL, 33 g, 0.34 mol) in methanol (2 L) was refluxed for 6 hr. The mixture was treated with a solution of sodium bicarbonate (29 g, 0.34 mol) in water (350 mL) and the resulting suspension was slowly cooled to 20° C. and stirred overnight. The suspension was filtered and the cake was washed with water (1 L). The solid was dried in a vacuum oven at 50° C. for 3 days to yield methyl 6-bromo-2-quinolinecarboxylate (294 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=9 Hz, 1H), 8.40 (d, J=2 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.97 (m, 1H), 3.93 (s, 3H). ES-LCMS m/z 267 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C(Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O1CCC[CH2:19]1>>[CH2:3]([O:9][CH:15]([CH3:14])[CH2:16][CH2:11][CH:12]=[CH2:13])[C:4]1[CH:19]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCCCCO
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=CCCC(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of sodium hydride (2.6g, 110 mmoles) in tetrahydrofuran (185 ml) under a nitrogen atmosphere was added a solution of 5-hexene-1-ol (10g, 100 mmoles) in tetrahydrofuran (15 ml). After stirring at room temperature for 0.5 hour, the mixture was briefly heated to reflux and then cooled. Benzyl bromide (21.4 g, 125 mmoles) was added, and the mixture was stirred at reflux for one hour. Stirring was continued overnight at room temperature, after which the mixture was concentrated on a rotary evaporator. The mixture was poured into water, and the aqueous layer was extracted with three portions of ether. The combined organic extracts were dried over sodium sulfate, filtered, and the solvent evaporated. Chromatography of the residue on silica gel using a gradient of 0 to 10% ethyl acetate-hexane as eluant gave the title product (11.2 g) as an oil. The structure was confirmed by 1H NMR spectrometry.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a round bottom flask, benzenesulfonyl chloride (83 mg, 0.54 mmol) was added dropwise a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (100 mg, 0.36 mmol) and pyridine (45 mg, 0.54 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as off-white solid (70 mg, yield: 46.5%). MS (ESI+APCI) M+1=418.2.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[F:1]
Reactant: CC(=O)Nc1cccc(F)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of N-(3-fluoro-2-methylphenyl)acetamide (72A) (1.71 g, 10.2 mmol) in acetic acid (15 mL) at 0° C. was added bromine (1.68 mL, 32.8 mmol) over 15 min. The mixture was stirred at rt for 2 h, and was then poured into ice (50 g). The mixture was filtered and concentrated under reduced pressure to give the title compound (2.26 g). LCMS: m/z 246 [M+H]+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:32](I)[CH3:33].C(O)(=O)C>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH2:32][CH3:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN(CC)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.05 g, 50% dispersion in oil) in DMF (100 ml) at 0° C. was added a solution of ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoate dropwise. The mixture was stirred at 0° C. for 1 hour, ethyl iodide (3.43 g) added and the mixture stirred at ambient temperature for 18 hours. The mixture was acidified with acetic acid, poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (3×100 ml), dried and evaporated. The residue was purified by chromatography eluting with 4% ethyl acetate/CH2Cl2 to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]benzoate (yield 6.61 g).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[S:38])=[CH:32][CH:31]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(C(=S)Nc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (196 mg, 0.73 mmol) was suspended in methylene chloride (10 ml), then neutralized with triethylamine (0.27 ml, 1.94 mmol). To the solution, 4-chlorophenyl isothiocyanate (140 mg, 0.83 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carbothioic acid (4-chlorophenyl)amide (128 mg, yield 40%) as a light brown powder.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:27]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-iodo-2′-deoxyuridine (5.0 g, 14 mmol) in 70 ml in dry N,N-dimethylformamide (DMF) was added imidazole (1.09 g, 16 mmol), followed by (2.41 g, 16 mmol) TBDMSCl at 0° C. The mixture was left in the ice bath and stirred overnight. The reaction was quenched with sat. aq. NaCl solution and extracted with EtOAc. After drying (MgSO4), the solvent was removed and the crude mixture was purified by chromatography on silica (EtOAc:petroleum ether 3:7). The product (33) (5.9 g, 90%) was obtained as a colourless solid. 1H NMR (d6DMSO) δ 0.00 (s, 3H, CH3), 0.79 (s, 9H, tBu), 1.88-1.97 (m, 1H, H-2′), 2.00-2.05 (m, 1H, H-2′), 3.59-3.71 (m, 2H, H-5′), 3.75 (br s, 1H, H-4′), 4.06 (br s, 1H, H-3′), 5.18 (d, J=4.0 Hz, 1H, OH), 5.98 (t, J=5.9 Hz, 1H, H-1′), 7.89 (s, 1H, H-6), 11.62 (s, 1H, NH). Mass (−ve electrospray) calcd for C15H25IN2O5Si 468.06 found 467.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[F:25])=[N:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:26][CH3:27].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[ClH:1].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:8]([O:26][CH3:27])[CH:9]=3)[N:14]=[CH:13][N:12]=2)=[C:19]([F:25])[CH:20]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCCl
Reactant: C1COCCN1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCN1CCOCC1
Product: Cl
Yield: 78 %

Procedure:
A solution of 7-(4-chlorobutoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (3.64 g, 8.87 mmol) in morpholine (70 ml) was heated at 110° C. for 2 hours. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride and methanol (92/8). The purified solid product was dissolved in methylene chloride and 3M ethereal hydrogen chloride was added. The volatiles were removed by evaporation, and the residue triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobutoxy)quinazoline hydrochloride (3.8 g, 78%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@H]1O[C@@H](NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 48 h

Procedure:
50 g of D-glucose were dissolved in 1,000 ml of hot ethanol and, after addition of 89 g of benzylamine, were left at room temperature for 48 hours. The mixture was then cooled with ice and the product was precipitated with petroleum ether. It was filtered off with suction, washed with ether and dried in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C@@H:51]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:52][OH:53]>CN(C=O)C>[OH:53][CH2:52][C@@H:51]([NH:50][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:54]([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of Intermediate 4 (1.4 g, 5.78 mmol) and triethylamine (1.611 mL, 11.56 mmol) in DMF (15 mL) was added HATU (2.242 g, 5.90 mmol). The reaction was stirred at 23° C. for 5 min, then (S)-2-amino-3,3-dimethylbutan-1-ol (0.711 g, 6.07 mmol) was added. The reaction was stirred at 23° C. for 15 min then concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.97 g) as a white solid. LCMS m/z=342.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H), 3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18](B(O)O)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O.C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:2]3[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cn1nccc1I
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1nccc1-c1cnn(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-iodo-1-methyl-1H-pyrazole (600 mg), [1-(4-fluorophenyl)-1H-pyrazol-4-yl]boronic acid (650 mg), tetrakistriphenylphosphine palladium (166 mg), 2 M sodium carbonate aqueous solution (2.9 mL), ethanol (3.0 mL) and toluene (6.0 mL) was stirred at 100° C. for 4 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=9:1 to ethyl acetate), so as to obtain the title compound (450 mg) in the form of a light yellow solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17]([NH2:20])(=[O:19])=[O:18].[CH:22]1([C:28]2[C:29]3[CH:30]=[CH:31][C:32]([C:50](O)=[O:51])=[CH:33][C:34]=3[N:35]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:37]=4[C:36]=23)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17]([NH:20][C:50]([C:32]1[CH:31]=[CH:30][C:29]2[C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:36]3[C:37]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:38]=4[CH2:39][N:40]([CH3:43])[CH2:41][CH2:42][N:35]3[C:34]=2[CH:33]=1)=[O:51])(=[O:19])=[O:18]
Reactant: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: COC(=O)CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C)Cc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
1.6 eq of 1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl salt was added to a mixture of 2.7 eq of DMAP, 1.6 eq of methyl(aminosulfonyl)acetate and the hydrochloride salt of 14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-benzodiazocine-11-carboxylic acid (from Example 4) in DCM (0.02 M). The reaction was stirred at RT overnight before being partitioned between aqueous HCl (1 N) and EtOAc. The organics were washed with saturated aqueous NaHCO3, water and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then purified by RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 30×50 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (18%).