Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4]N=C1.[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][N:14]2[CH:20]=1)=[O:10])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+].[C:27](#[N:29])C>>[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([N:1]3[CH:5]=[CH:4][CH:27]=[N:29]3)=[CH:15][N:14]2[CH:20]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cn2cc(I)ccc2n1
Reactant: c1c[nH]cn1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cn2cc(-n3cccn3)ccc2n1
Yield: 31 %

Procedure:
A mixture of sulfuric acid (0.5 mL), acetic acid (12 mL) and water (2 mL) was added to a reaction flask containing 2-aminopyridine (2.0 g, 21.26 mmol) and the solution was stirred for 5 minutes. NaIO4 (1.81 g, 8.5 mmol) followed by 12 (2.16 g, 8.5 mmol) was added into the reaction flask and stirred at 80° C. for 4 hrs. The reaction mixture was cooled to ambient temperature, diluted with cold water, basified with 20% aqueous KOH solution and extracted with DCM. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. Purification by column chromatography (using silica gel 60-120 and 8% EtOAc in hexane as eluent) and subsequent recrystallisation from ethanol afforded 53 g (58.6% Yield) of 5-iodo-pyridin-2-ylamine. Ethyl bromopyruvate (4.89 g, 25.11 mmol) was added to solution of 5-iodo-pyridin-2-ylamine (5.0 g, 22.83 mmol) in DMF (25 mL) and stirring was continued at 80° C. for 2 hrs. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by recrystallisation from methanol to afford 4.2 g (57.8% Yield) of 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of imidazole (513 mg, 7.5 mmol), cuprous oxide (71 mg, 0.5 mmol), 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.6 g, 5.02 mmol), salox (137 mg, 1.0 mmol) and cesium carbonate (3.27 g, 10.05 mmol) in ACN (2 mL) in a seal tube were subjected to reaction in a microwave reactor (time: 15 min, temp: 85° C., power: zero, pressure: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (using neutral alumina and 0.2% MeOH in DCM as eluent) to afford 400 mg (31% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.97 mmol) in 8N aqueous HCl (3 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford 130 mg (58.5% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 30.6 %

Procedure:
4.5 g of 1-(2-chloroethyl)-3-n-propyl-3-D-glucopyranosylurea are dissolved in 20 ml of formic acid, and 2.8 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 20 ml of methanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to said mixture, and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography(Solvent: methanol-chloroform(1:5)). 1.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][O:19][CH3:18])[CH:26]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: COCc1cccc(B(O)O)c1
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 91 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) and 3-(methoxymethyl)phenylboronic acid. Yield: 91%. 1H NMR (400 MHz, DMSO): δ 0.72-0.74 (d, 6H), 1.46 (s, 6H), 1.68 (m, 1H), 2.83 (t, 2H), 3.29 (s, 3H), 4.45 (s, 2H), 7.27-7.29 (d, 1H), 7.33 (t, 1H), 7.36-7.38 (d, 2H), 7.41 (t, 1H), 7.53-7.55 (d, 2H), 7.58-7.60 (d, 2H). MS (M+H, 340).
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[CH2:26][C:25]2[C:20](=[CH:21][C:22]([C:27]#[N:28])=[CH:23][CH:24]=2)[NH:19]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].P(Cl)(Cl)Cl>O1CCCC1>[ClH:1].[OH:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[CH:6][N:7]=1)=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[CH:21]=2
Reactant: CN1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClP(Cl)Cl
Product: CN1CCN(Cc2ccc(-c3c(O)[nH]c4cc(C#N)ccc34)nc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.9 %

Procedure:
To a suspension of 1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-methylpiperazine (0.145 g, 0.60 mmol) and 2-oxoindoline-6-carbonitrile (0.100 g, 0.63 mmol) in tetrahydrofuran (3 mL), was added sodium bis(trimethylsilyl)amide (1.4 mL, 1.4 mmol). The mixture was stirred for 5 min at room temperature and then heated in a microwave oven at 110° C. for 10 min. The mixture was quenched with methanol (2 mL) followed by evaporation to dryness. The dry product mixture was dissolved in ethyl acetate/acetonitrile, (1:1, 5 mL), is and phosphorus trichloride (0.5 mL, 5.73 mmol) was added. The mixture was stirred at 60° C. for 3 h and then concentrated in vacuo. The residue was purified on a silica gel column using a gradient dichloromethane/methanol, (100:1 to 2:1), as the eluent. The resulting yellow solid was dissolved in dichloromethane/methanol, (9:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting yellow crystals were collected by filtration and washed with diethyl ether to obtain 0.025 g (9% yield) of the title compound: MS (ESP) m/z 348 (M++1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@:19]1(CO)[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:19]1[CH:20]=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@]1(CO)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=O
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A solution of oxalyl chloride (1.71 g, 13.5 mmol) in methylene chloride (50 ml) was cooled to -78° C. and a solution of dimethyl sulfoxide (2.18 g, 27.1 mmol) in methylene chloride (5 ml) was added thereto. This solution was stirred for 10 minutes. To this solution was added a solution of the alcohol crude product obtained by the above reaction in methylene chloride (10 ml). The mixture was stirred for 10 minutes, and then triethylamine (4.76 ml, 33.9 mmol) was dropwise added at the same temperature. The reaction solution was gradually warmed to 20° C. over a period of 2 h. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=1:4) to give the title compound (829 mg, yield: 84.5%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([C:10](=[O:13])[NH:11][CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([N:3]1[CH2:9][CH:8]([C:10](=[O:13])[NH:11][CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([S:18]([NH:21][C:29]([NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:30])(=[O:19])=[O:20])=[CH:17][C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCc2cc(S(N)(=O)=O)ccc2C(C(=O)NC)C1
Reactant: O=C=NC1CCCCC1
Product: CCN1CCc2cc(S(=O)(=O)NC(=O)NC3CCCCC3)ccc2C(C(=O)NC)C1

Procedure:
By the reaction of 3-ethylmethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-[(3-ethylmethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]-3-cyclohexylurea. The starting material can be prepared by first reacting ethylmethylamine with phosgene to give ethylmethylcarbamoyl chloride and subsequently bringing the latter to reaction with 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4]CC1.[Br:8][C:9]1[CH:10]=[C:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>>[Br:8][C:9]1[CH:10]=[C:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[NH:7][CH2:1][CH:6]1[CH2:4][CH2:5]1
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: NC1CCCCC1
Product: NS(=O)(=O)c1ccc(NCC2CC2)c(Br)c1

Procedure:
Example 238a was prepared according to the procedure used for the preparation of Example 96a, substituting cyclopropylmethanamine for cyclohexanamine, and 3-bromo-4-fluorobenzenesulfonamide for Example 86a, respectively, to provide the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>C(O)C.[Pd].C1CCCCC=1>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([C:22]([OH:24])=[O:23])[NH2:11])=[CH:19][CH:18]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
N-Benzyloxycarbonyl-O-methyl-L-tyrosine (5.7 g, 17.3 mmol) was dissolved in ethanol (50 ml) and the solution added to a suspension of 10% palladium on charcoal (100 mg) in cyclohexene (10 ml). The reaction was then heated at reflux for 1 h, allowed to cool to ambient temperature, filtered, and the filtrate concentrated to give O-methyl-L-tyrosine (1.4 g, 43%) as a white solid which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(Cl)Cl.[CH3:17][CH2:18]N(C(C)C)C(C)C.[F:26][C:27]1([F:39])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([C:36](Cl)=[O:37])[C:29]=2[O:28]1>CN(C)C1C=CN=CC=1.CC(O)C.C(Cl)Cl>[CH2:17]([O:12][C:11]([C:2]1([NH:1][C:36]([C:35]2[C:29]3[O:28][C:27]([F:39])([F:26])[O:31][C:30]=3[CH:32]=[CH:33][CH:34]=2)=[O:37])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)=[O:13])[CH3:18]
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OC(F)(F)O3)Cc2ccccc2C1
Reaction time: 432 h
Yield: 112.9 %

Procedure:
A 100 mL round bottom flask is charged with 2-aminoindan-2-carboxylic acid (340 mg, 1.66 mmol) and dry DCM (6 mL). A stirring bar is added and stirring is initiated. DIPEA (0.46 mL, 2.65 mmol) is added. 2-[(2,2-difluoro-benzo[1,3]dioxole-4-carbonyl chloride (438 mg, 1.99 mmol) is added. 4-Dimethylaminopyridine ([MFCD0006418], 2 mg, cat.) is added. The reaction is capped. After 18 days, tlc analysis (silica, 5% iPrOH/DCM) indicates that the starting is completely consumed. The contents of the reaction flask are transferred to a reparatory funnel and diluted with EtOAc (60 mL). This is washed with dilute aqueous HCl (2×25 mL), saturated aqueous NaHCO3 (2×25 mL), and brine (25 mL), dried over MgSO4, filtered and evaporated by pumping to constant weight to yield 0.73 g of dark brown foam. This is diluted with DCM and applied to a silica column (40 g) on an ISCO Companion. The column is eluted with 3 column volumes of 10% EtOAc-heptanes followed by a linear gradient to 50% EtOAc/heptanes over 10 Column Volumes. And then 90% EtOAc/heptanes for 2 Column Volumes. 17 mL fractions of UV positive eluent are collected. Fraction 8-10 are combined and evaporated by pumping to constant weight to give light orange solid (0.57 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[O:11]([C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 3,5-dimethoxyphenol (6.73 g, 43.7 mmol) in anhydrous dimethylformamide (50 mL) were added imidazole (5.95 g, 87.4 mmol) and t-butylchlorodiphenylsilane (15.0 g, 54.6 mmol), and the mixture was stirred at 50° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (1:2). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene as a colorless crystalline powder (melting point: 95.5-96.5° C.) (16.14 g, yield: 94%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: NCC1CCCO1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCC1CCCO1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1CCN(C2C3CNC(C4N=CC=CN=4)CC=3N=C(C3C=CC(N)=CC=3)N=2)C[CH2:32]1.[CH3:60][N:61]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62]1.C1(CN)CC1>>[CH3:60][N:61]1[CH:65]=[CH:64][C:63]([NH:66][C:32]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])=[N:62]1
Reactant: Cn1ccc(N)n1
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC(c2ncccn2)C3)cc1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Agent: NCC1CC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccn(C)n3)cc2)nc2c1CCN(c1ncccn1)C2

Procedure:
The title compound lg was prepared by the general procedure of Example 30 substituting (S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline for 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)aniline and 1-methyl-1H-pyrazole-3-amine for cyclopropylmethylamine. LC-MS: m/z=+527 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>CC(C)=O.ClCCl>[C:21]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:23])[CH3:22]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
4-Hydroxy-3-nitro-benzoic acid (5.49 g, 30 mmol) was dissolved in acetone (10 ml), triethylamine (10 ml) and acetic acid anhydride (5.67 ml, 60 mmol). The solution was stirred for 24 h at rt. The reaction mixture was added dichloromethane (100 ml), ice (20 g) and acidified by addition of concentrated hydrochloric acid. The aqueous phase was extracted with dichloromethane (2×25 ml). The combined organic phases were stirred with sodium sulphate added activated carbon, filtered and evaporated. Recrystallisation from EtoAc:Heptane gave 3.45 g (51%) pure material.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[C:12]([CH3:19])[C:11]([O:10][CH3:9])=[CH:16][C:15]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1ccc(OC)c(C)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(C)=O)c(OC)cc1C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
A suspension of 17.52 g of aluminium chloride in a mixture of 100 ml of CCl4 and 100 ml of DCM is cooled to +4° C. under nitrogen, and 10.4 g of acetyl chloride are added dropwise, followed by a solution of 20 g of 2,5-dimethoxytoluene in 20 ml of DCM. After stirring for 4 hours at +4° C., the reaction medium is poured onto ice to which a few ml of concentrated HCl have been added and the mixture is left stirring for 30 minutes. The phases are separated by settling, the aqueous phase is extracted with DCM and the combined organic phases are washed with aqueous 5% NaCO3 solution, dried over MgSO4 and evaporated. The product crystallizes, and is triturated from 150 ml of heptane, filtered off and then washed with heptane to give 21.03 g of the expected compound: m.p.=75-77° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>CCCCCC>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
6-Nitro-3H-quinazolin-4-one 4a (18.88 g, 99.40 mmol) was dissolved in phosphoricchloride (31.03 g, 149 mmol). The mixture was warmed up to 160° C., and stirred for 3 hours. The reaction mixture was added to 250 mL of n-hexane while hot, stirred and a lot of the solid was precipitated from the solution, filtered, the filter cake was washed with n-hexane, dried under vacuum to obtain the title compound 4-chloro-6-nitro-quinazoline 4b (18.14 g, yield 87.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[H][H]>[Pt].CN1CCOCC1>[OH:9][NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Pt]
Solvent: CN1CCOCC1
Product: ONc1cccnc1Cl
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A mixture of 18.3 g (115 mmol) of 2-chloro-3-nitropyridine and 300 ml of N-methylmorpholine was hydrogenated at room temperature and a hydrogen pressure of approximately 1.1 bar in the presence of 3 g of 5% platinum/charcoal (55.5% of water [Degussa]). After approximately 1.5 hours, the hydrogen uptake had ceased. The catalyst was removed by filtration through kieselguhr. The filtrate obtained was freed from solvent at approximately 45° C. under reduced pressure. Any remaining N-methylmorpholine was distilled off with 200 ml of Solvesso (Esso) under reduced pressure using a 20 cm column. The crystallizate which remained was taken up in 200 ml of n-hexane, filtered off with suction and washed with n-hexane. 15.9 g (96%) of the title compound were obtained as brown crystals.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>CS(C)=O>[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)OCC

Procedure:
Diethyl malonate was added dropwise at 20°-25° C. to a stirred suspension of sodium hydride (1 equi) in dry DMSO. The mixture was stirred until the evolution of hydrogen had ceased (ca. 1 hour), then a solution of p-isopropylbenzyl bromide (1 equiv.) (prepared from p-isopropylbenzyl alcohol and PBr3) in dry DMSO added dropwise with stirring. After stirring at room temperature for 1.5 hours the mixture was heated on the steam bath for 0.5 hour until a clear solution was obtained. The mixture was poured onto ice, extracted several times with ether and the extracts combined and washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residual oil was distilled, collecting the fraction b.p. 160°-170° (2-3 mm).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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.O>[CH:12]([C:4]1[CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]=1[NH2:6])([CH3:14])[CH3:13]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1N
Yield: 56.8 %

Procedure:
4-bromo-2,6-diisopropylaniline (16 g, 62.5 mmol), (PPh3)4Pd (2.2 g, 1.9 mmol), phenylboronic acid (11 g, 87.5 mmol), K3PO4 (26 g, 187 mmol), 400 mL of toluene and 40 mL of water were charged and heated up to reflux for overnight. The reaction mixture was purified by column and distillation method to give 9 g liquid (57% yield).