Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[NH2:25][CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:25][CH:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]2[OH:35])[CH:6]=1
Reactant: NC1Cc2ccccc2[C@@H]1O
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-2-amino-indan-1-ol.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4](OCC)=[O:5])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[CH3:28][C:29]1([CH3:37])[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH:30]1[OH:36]>>[C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:36][CH:30]1[CH:31]([CH3:35])[CH2:32][CH2:33][CH2:34][C:29]1([CH3:37])[CH3:28])=[O:5])#[N:2]
Reactant: CC1CCCC(C)(C)C1O
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CCCC(C)(C)C1OC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 74 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 ml of 2,2,6-trimethylcyclohexanol and 4 g of Na2CO3 were reacted with one another at 184-186° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 3 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, it was distilled under reduced pressure, giving 55 g (74%) of 2,2,6-trimethylcyclohexyl 2-cyano-3,3-diphenylacrylate [λmax=304 nm, E11=351] as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]([CH3:36])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:36])[CH3:33])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.069 mmol) in 10 mL of dichloromethane is added 1 mL of acetone and NaB(OAc)3H (30 mg, 0.138 mmol). The resulting mixture is stirred at room temperature for 18 h. Following purification by preparative LCMS gave 7-cyclopentyl-2-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 61%). MS (ESI) m/z 477.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)=[O:4].[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:13])[N:20]2[CH2:21][CH2:22][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[CH2:6]1)=[O:4]
Reactant: COCC1(C(=O)OC)CCN(CC(=O)O)C1
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC1(C(=O)OC)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a solution of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 97) (0.21 mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10, see Example 1 Step 7) (0.21 mmol), O-(7-azabenzotriazol-1-yl-)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU) (78 mg, 0.21 mmol) in dry DMF (2 ml) was added N,N-diisopropylethylamine (108 μl, 0.62 mmol). The reaction mixture was stirred for 4 hours, and evaporated to a residue that was partitioned in ethyl acetate and saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried over magnesium sulfate. Evaporation of solvent provided a crude product which was chromatographed with 5% methanol in dichloromethane to furnish the title compound (97 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-(6-chloropyridin-3-ylcarbonyl-amino)-N-(5-chloropyridin-2-yl)benzamide (0.2 g) and morpholine (2 mL) in DMSO (2 mL) was heated at 80° C. in a sealed tube overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, sodium bicarbonate, and dried over sodium sulfate. After evaporation of the solvent, the product was purified by RPHPLC [ethyl acetate/hexane (3:7)]. Yield=0.054 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.COC(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:13])=[O:9])[S:5][CH:6]=1
Reactant: COC(Cl)Cl
Reactant: O=C(O)c1cc(Br)cs1
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
A suspension of 4-bromothiophene-2-carboxylic acid (47.0 mmol crude, from previous step) in α,α-dichloromethyl methyl ether (13.0 mL, 150 mmol) was slowly heated to reflux. As the reaction mixture was heated a pale brown solution formed, and gas evolution was evident. After stirring at a gentle reflux for 5 hours, the reaction solution was allowed to cool and was then concentrated under reduced pressure to afford 4-bromothiophene-2-carbonyl chloride as a brown liquid. This liquid was dissolved in CH2Cl2 (150 mL) and the reaction flask was cooled in an ice bath. The cold reaction solution was treated with a small amount of 4-(N,N-dimethylamino)pyridine, N,O-dimethylhydroxylamine hydrochloride (5.5 g, 56 mmol), and finally N,N-diisopropylethylamine (14 mL, 80 mmol). After stirring for 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 hours, the pale brown reaction solution was quenched by the addition of ice-cold H2O, and diluted with CH2Cl2 (500 mL). The layers were separated, and the organic layer was washed with 1 N HCl (100 mL), H2O (50 mL), and saturated aqueous NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford a brown liquid. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane on silica. The product peak was collected to afford 4-bromothiophene-2-carboxylic acid methoxymethylamide as a yellow oil. (9.9 g, 83% yield over three steps). 1H-NMR (400 MHz, CDCl3): δ 7.83 (1H, d, J=1.5 Hz), 7.45 (1H, d, J=1.5 Hz), 3.78 (3H, s), 3.37 (3H, s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.CN(C)[CH:41]=[O:42]>O1CCCC1>[CH2:34]([O:33][CH2:32][C@H:31]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][N:22]1[CH2:21][C:17]1[C:16]([CH2:36][CH3:37])=[N:15][N:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]([CH:41]=[O:42])=[CH:8][C:9]=2[CH3:38])[C:18]=1[CH2:19][CH3:20])[CH3:35]
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(C=O)cc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 155.4 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.043 ml, 0.11 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (50 mg, 0.098 mmol) in anhydrous tetrahydrofuran (0.2 ml) was added dropwise. After stirring at -78° C. for 10 minutes, anhydrous N,N-dimethylformamide (0.023 ml, 0.29 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The reaction quenched by addition of aqueous ammonium chloride (1 ml) and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was washed with an equal volume solution of aqueous ammonium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil (70 mg). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl actate/hexane=1:4 in volume) afforded the title compound (14 mg) as a faint yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCI
Reactant: COc1cccc(CCNCCc2c[nH]cn2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCc1c[nH]cn1
Yield: 31.1 %

Procedure:
A stirred mixture of 3.2 g of the product of Step B, 5.1 g of potassium carbonate, 3.4 g of 1-iodopropane and 64 ml of acetone was refluxed under an inert atmosphere for 19 hours and the acetone was evaporated. 100 ml of water and 2 ml of sodium hydroxide were added to the mixture which was then extracted 3 times with 50 ml of methylene chloride. The combined organic phases were washed with 100 ml of water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the 3.6 g of oil residue were chromatographed over silica gel to obtain 900 mg of N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-imidazol-4-ethanamine in the form of a yellow oil which was used as is for the next step. C.C.M. over silica (7-3 CHCl3 -Methanol): Rf=0.20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:14]=2[CH3:24])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: [6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridin-2-yl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][CH2:23][CH:24]([NH2:27])[CH2:25][CH3:26]>>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:27][CH:24]([CH2:23][OH:22])[CH2:25][CH3:26])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(N)CO
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Product: CCC(CO)Nc1nc(NCc2ccccc2)c2[nH]nc(C(C)C)c2n1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
The mixture of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine XVI (100 mg, 0.331 mmol) and 2 mL of 1-(R,S)-(hydroxymethyl)propylamine was heated at 120° C. for 3 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed on silica gel. The mixture of chloroform/methanol (97/3) was used as a mobile phase. Yield=83.5%; white syrupy; MS (ES+): 355.3 (100%, M+H+). 1H-NMR (400 MHz, CDCl3): 0.96 t (3H, J=7.2 Hz, CH3CH2), 1.299 d (3H, J=7.1 Hz), 1.307 d (3H, J=7.1 Hz), 1.6 m (2H), 3.20 sept (1H, J=7.1 Hz), 3.55-3.80 m (3H), 4.74 bs (2H), 7.22-7.35 m (5H).
Reaction SMILES: C(N=C([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)OC1C=CC=CC=1)#N.[NH3:44]>CO>[C:29]([N:34]=[C:35]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[NH2:36])#[N:44]
Reactant: N
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Solvent: CO
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(N)=NC#N)CC1
Yield: 91 %

Procedure:
Phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (100 mg, 0.175 mmol) and a solution of ammonia in methanol (2 mL, 1.4 M) was stirred at ambient temperature for 20 hours. After evaporation of the excess ammonia and the solvent, the residue was subject to flash chromatography (Mega Bond Elut Si, MeOH/EtOAc, 10% to 40%) to afford N′-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidamide as amorphous solid (79 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 7.68-7.65 (m, 1H), 7.42-7.34 (m, 2H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 6.11 (s, 2H), 4.65 (t, J=8.5 Hz, 1H), 3.82-3.78 (m, 2H), 3.27-3.20 (m, 4H), 2.53 (s, 3H), 2.45-2.25 (m, 4H), 1.96-1.84 (m, 10H), 1.64 (d, J=7.5 Hz, 2H). HRMS m/z (M+H)+ calcd: 496.3189, obsd: 496.3181.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1OC)([O-:3])=[O:2].[Cl-].[Cl-].[Ca+2].[CH2:20]([CH:22]([NH2:25])[CH2:23][CH3:24])[CH3:21]>>[CH2:20]([CH:22]([NH:25][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH3:24])[CH3:21]
Reactant: COc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reactant: CCC(N)CC
Agent: [Ca+2]
Agent: [Cl-]
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reaction time: 24 h
Yield: 86.6 %

Procedure:
To a suitable reaction vessel equipment with a thermometer and mechanical stirrer was introduced 24 g 2,6-dinitro-3,4-dimethylanisole 94% (0.1 moles), 0.55 g CaCl2 (0.005 moles), and 43.5 g (0.5 moles) 1-ethyl propylamine. The reaction mixture was stirred at a temperature of 25°-30° C. The progress of the reaction was followed by periodically withdrawing samples and analyzing for starting product and the new product formed. During 24 hours the starting product disappeared and the N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline is gradually formed. After completion of the reaction as indicated by vapor phase chromatography, the excess of 1-ethyl-propylamine was recovered from the reaction mixture by distillation. The residue was dissolved in dichloromethane and the solution was successively washed with 5% aqueous hydrochloric acid, 5% aqueous sodium hydroxide and then by water to neutral and dried. The solvent is next recovered by distillation leaving an oily product which solidified. (25.2 g 96.6%) with a yield of 86.6%.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH3:23])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-phenylglycinol (1.00 g, 7.3 mmol) and triethylamine (1.02 mL, 7.3 mmol) in CH2Cl2 (50 mL) at 0° C. was slowly added 2-chloropropionyl chloride (0.72 mL, 7.3 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=228 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH:16]([O:18][Si:19]([CH3:29])([CH3:28])[C:20]([CH3:27])([CH3:26])[CH2:21]C(C)(C)C)[CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH:16]([O:18][Si:19]([C:20]([CH3:27])([CH3:26])[CH3:21])([CH3:29])[CH3:28])[CH2:15][C:14]2=[S:42])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CC(O[Si](C)(C)C(C)(C)CC(C)(C)C)CC2=O)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(S(=O)(=O)N2CC(O[Si](C)(C)C(C)(C)C)CC2=S)cc1

Procedure:
A mixture of 3.14 g of the product obtained in Stage A above 1.55 g of Lawesson reagent in 40 cm3 of toluene is taken to reflux for 4 hours. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica (eluant: ethyl acetate - hexane 3-7). 2.45 g of desired product is obtained. M.p.=136° C. (after dissolution in ethyl acetate, filtration, evaporation to dryness, impasting in hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:17])[C:5]2([CH2:20][CH3:21])[CH2:18][CH3:19]>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH:14]([CH3:15])[CH3:16])[C:6](=[O:17])[C:5]2([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc([N+](=O)[O-])c(N)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(CC)C(=O)N(C(C)C)c2cc(N)c(N)cc21
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 5-amino-3,3-diethyl-1-isopropyl-6-nitro-1,3-dihydro-indol-2-one (1.9 g, 6.52 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration the solvent was evaporated and the residue triturated with iso-hexane to yield 1.7 g 5,6-diamino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (6.50 mmol, 99%).
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11]>C(O)C>[CH3:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:2][NH2:3]
Reactant: COCCOCCBr
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCCOCCNN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of hydrazine monohydrate (44.0 mL, 1.00 mol) in ethanol (75 mL) at 0° C. in an ice-water bath was added 1-(2-bromoethoxy)-2-methoxyethane (13.6 mL, 0.100 mol) drop-wise over 20 minutes. The reaction was then allowed to warm to room temperature and stir for 5 minutes and then heated to 40° C. in a preheated oil bath for 12 hours. The reaction was then cooled to room temperature and concentrated to remove the ethanol. The remaining aqueous layer was extracted with methylene chloride (2×100 mL) and diethyl ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to provide [2-(2-methoxyethoxy)-ethyl]-hydrazine as a light yellow oil (10.29 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[CH2:11][C:5]=2[CH:4]=1)#[N:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[NH4+].[OH-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)c1ccccc1S2
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Cc3cc(C#N)ccc3Sc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyano-10-oxo-dibenzo[b,f]thiepine (0.10 g, 0.40 mmol) in dry toluene (10.00 mL), was added methyl piperazine (0.21 mL, 1.80 mol) followed by the dropwise addition of TiCl4 (1 M in toluene, 1.60 mL, 1.6 mol) via syringe. The mixture was stirred at room temperature for 30 min then refluxed for 5 h. The reaction mixture was cooled, dumped into conc NH4OH and extracted with CHCl3. The combined organic phases were dried (MgSO4) and concentrated in vacuo to dryness. The crude material was chromatographed (20%MeOH/EtOAc) to give 2-cyano-10-(4-methyl-piperazinyl)-dibenzo [b,f]thiepine; yield 0.05 g, (5%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24]N3CCCCC3)=[CH:5][C:4]=2[N:3]=1.C(O[C:35](=[O:37])[CH3:36])(=O)C>ClCCl>[C:35]([N:3]1[CH2:4][CH2:9][CH2:10][CH2:11][CH:2]1[O:24][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CCOCc1nc2c(N)nc3cc(ON4CCCCC4)ccc3c2n1CC(C)(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OC4CCCCN4C(C)=O)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
1-[4-Amino-2-(ethoxymethyl)-7-(piperidinyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (from Part A) was slurried in dichloromethane (11 mL). Acetic anhydride (0.105 mL, 1.03 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The resulting solid was covered with diethyl ether for one week. Filtration of the solid provided 0.130 g of 1-[7-[(1-acetylpiperidinyl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as red-tan crystals, mp 162-164° C.