Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[C:24]3[C:23](=[N:25][OH:26])[CH2:22][CH2:21][CH2:20][C:19]=3[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]=2[CH3:33])=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[C:1]([O:26][N:25]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:33])=[C:16]([S:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[C:24]1=2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NOC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (4.33 mL, 45.8 mmol) was added to a slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (15 g, 38.2 mmol) in xylene (33.75 mL) and acetic acid (3.75 mL) and the mixture stirred at r.t. for around 20 mins. A sample of the title compound was isolated by filtration and dried at 40° C. m/z 435/437 (MH+); 1H NMR: 7.27-7.23 (2H, m), 7.00-6.96 (2H, m), 4.92 (2H, s), 4.19 (2H, q, J=7.1 Hz), 2.68-2.59 (4H, m), 2.19 (3H, s), 1.90 (3H, s), 1.89-1.81 (2H, m), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2]([C:25](=[O:26])[NH:12][C:9]32[CH2:11][CH2:10]3)=[CH:7][CH:6]=1
Reactant: NC1(c2cc(Cl)ccc2Br)CC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NC2(CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 1-(2-bromo-5-chlorophenyl)cyclopropanamine (2 g, 8.1 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3.1 g, 24.3 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. The reaction mixture was diluted with EtOAc (300 mL), and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (700 mg, yield 44.6%) as a yellow solid. MS: 193.8 (M+H+, 1C1).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8]([NH2:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].O>C1(C)C=CC=CC=1>[C:8]([NH:14]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCC(=O)C(=O)O
Reactant: CC(C)CC(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(\NC(=O)CC(C)C)C(=O)O
Reaction time: 5 h

Procedure:
A solution of 1.07 g (10.5 mmole) of 2-ketobutyric acid and 0.71 g (7.0 mmole) of isovaleramide in 15 ml of toluene was stirred under reflux with collection of H2O in a small Dean-Stark trap. After 5 hrs, the solution was cooled, resulting in fairly heavy crystallization. After standing, the solid was collected on a filter and washed with toluene and then with CH2Cl2. Yield of white crystals=0.47 g, mp 172°-174° (slight prelim. softening). The material was recrystallized from diisopropyl ketone. Tlc (4:1 toluene-AcOH) now showed only a faint trace of the other isomer. Yield of white crystals=0.32 g (25%), mp 175° (slight prelim. softening). NMR indicated essentially exclusively Z-isomer.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[N:11][CH:12]=1
Reactant: BrBr
Reactant: COc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 51 %

Procedure:
Bromine (0.99 ml) was added dropwise to a stirred suspension of sodium acetate (1.59 g) and 2-methoxypyridine (1.93 ml) in acetic acid (10 ml). The reaction mixture was stirred at room temperature for 25 minutes, then at 80° C. for 2.5 h. The mixture was then allowed to cool and poured into ice-water, neutralised with 2M sodium hydroxide and extracted with ether. The combined extracts were dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with 5% ethyl acetate in hexane to give 5-bromo-2-methoxypyridine as a colourless oil (1.75 g, 51%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1csc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Br)n2)CC1
Temperature: 20 °C
Yield: 92.8 %

Procedure:
2-bromothiazole-4carboxylic acid (1.31 g, 6.3 mmol) was combined with tert-butyl piperazine-1-carboxylate (1.2 g, 6.3 mmol) in DCM (15 mL), and then stirred at 20° C. until it formed a clear solution. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.2 g, 6.3 mmol) was then added, and the reaction was stirred at 20° C. for 2 hours. The reaction was concentrated in vacuum, before transferring it to a separation funnel with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, NH4Cl, and then with brine. After drying the organic layer with MgSO4, it was concentrated in vacuum to yield compound 72 (2.2 g, 91%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (1H, s), 3.61 (4H, m), 3.38 (4H, m), 1.42 (9H, s) ppm; LCMS-ESI (POS), M/Z, M+1-C3H9: Found 320.0.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[N:10]([CH3:19])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:17][N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][S:30]([C:24]4[C:25]([CH3:29])=[N:26][N:27]([CH3:28])[C:23]=4[Cl:22])(=[O:31])=[O:32])=[CH:3][CH:4]=3)=[N:8][C:9]=2[N:10]([CH3:19])[C:11]1=[O:18]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Cn1c(=O)c2[nH]c(Cc3ccc(N)cc3)nc2n(C)c1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of crude 8-(4-amino-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (0.2 mmol) in pyridine (2 mL) at 0° C. was added 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.2 mmol) and the mixture left to stir and warm slowly to ambient temperature overnight. The reaction mixture was poured into ethyl acetate, washed with 1M aqueous hydrochloric acid until all pyridine was removed from the organic phase and the combined aqueous washings back extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to give an orange solid. Purified by trituration with warm acetonitrile to give 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide as a pale orange solid (51%); EI-HRMS m/e calculated for C19H20ClN7O4S (M+) 477.0986, found 477.0994.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](N(OC)C)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:26][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](=[O:21])[CH3:26])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c2ncccc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C=Cc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-N-methoxy-N-methyl-5-vinylquinoline-7-carboxamide (32 mg, 0.095 mmol) in tetrahydrofuran (0.2 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (0.20 mL, 0.29 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour, quenched with sat. ammonium chloride. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to dryness. The crude product was used directly in the next step (26 mg, 94%). LCMS calculated for C19H15FNO (M+H)+: m/z=292.1; Found: 292.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:19][CH2:18][CH2:17][CH2:16][C@@:13]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:38])=[O:37]
Reactant: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a solution of (R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.046 mmol) in CH2Cl2 (2 mL) was added Et3N (13 μL, 2 equiv) and MsCl (6 μL, 1.55 equiv) at 0° C. After 5 min, the mixture was warmed to rt and stirred for 1 h. The mixture was concentrated, acidified with 5% aq HCl to pH=˜6 and purified by preparative HPLC to afford 3-((R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (6.8 mg, 29%). LC-MS (3 min) tR=1.83 min., m/z 514, 516 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.8 g, 21.45 mmol) in CH2Cl2 (59 mL, 0.2M) was added 4N HCl/Dioxane (21 mL). The solution was stirred overnight forming a solid. The solid was crushed thoroughly with a glass rod and sonicated to release starting material trapped in the solid. Additional 4N HCl/Dioxane (21 mL) was added and stirred for another 2 hours at room temperature in which LCMS showed no starting material. The suspension was filtered in a Buchner funnel lined with filter paper. The mother liquor was saved because it contained <5% of product. The solid was transferred to a 500 mL beaker and HPLC water was added until the solid dissolved completely. The pH was adjusted to 10 with the addition of solid Na2CO3. The water solution was extracted with CH2Cl2 (5×200 mL) or until LCMS showed no product in the aqueous layer. The CH2Cl2 solution was dried over Na2SO4 and concentrated. The crude product, re-dissolved in CH2Cl2 (10 mL) and MeOH (1 mL), was purified on a silica gel column eluting with CH2Cl2/MeoH/NEt3 system (Biotage 40+Column: equilibrium 600 mL CH2Cl2 100% giving byproduct, segment 1: 1200 mL 10% MeOH/CH2Cl2 linear, segment 2: 2400 mL 10% MeOH/CH2Cl2 step, segment 3: 2400 mL 9% MeOH/1% NEt3/CH2Cl2). The desired fractions were collected to provide 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (7.19 g, 75% combined yield, white solid). MS m/e 450 (M+1)+. 1H NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.76 (s, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 7.45 (m, 1H), 6.90 (s, 1H), 6.10 (m, 1H), 5.55 (bs, 2H), 4.14 (m, 1H), 3.05 (m, 2H), 2.58 (m, 2H), 1.94 (m, 2H), 1.80 (d, 3H), 1.76 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 86 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.171 g, 0.371 mmol) was dissolved in dichloromethane (3.5 mL), and the solution was treated with triethylamine (0.103 mL, 0.741 mmol) and benzenesulfonyl chloride (0.0570 mL, 0.446 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-benzenesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.192 g. yield 86%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:8]2.[C:27]([C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1)#[N:28]>>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:32]([C:29]3([C:27]#[N:28])[CH2:31][CH2:30]3)=[O:33])=[CH:25][CH:26]=1)[CH2:4]2
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCOCC2C3CC4CC(C3)CC2C4)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCC3C4CC5CC(C4)CC3C5)cc2)CC1
Yield: 96.2 %

Procedure:
General procedure E was used to convert 1.30 mmol of 13d and 1.95 mmol of 1-cyanocyclopropanecarboxylic acid to 1.25 mmol (96%) of the title compound.
Reaction SMILES: Cl.C1([C@H]([NH:10][C@H:11]([CH3:24])[CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=2)C)C=CC=CC=1.C([O-])=O.[NH4+]>>[NH2:10][C@H:11]([CH3:24])[CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: COC(=O)Cc1cccc(C[C@@H](C)N)c1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A solution of methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride (Preparation 23) (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75° C. in the presence of 20% palladium hydroxide-on-charcoal (Pd(OH)2/C, 2.00 g). After 90 minutes the reaction mixture was cooled to room temperature, filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (100 mL) and 880 ammonia (100 mL) and the organic phase separated. The aqueous phase was extracted dichloromethane (100 mL) and the combined organic extracts dried (magnesium sulfate) and reduced in vacuo to give the title compound as a colourless oil (4.78 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:39](=O)[CH2:40][CH:41]([CH3:43])[CH3:42].CC(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:13]=[C:14]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)C(CC(C)C)c1cc(NCc2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C(C)(C)C)cc2)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 2-[5-(4-tert-Butyl-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester, compound 37a, (0.06 g, 0.11 mmol), isovaleraldehyde (0.36 mL, 3.3 mmol), AcOH (0.01 mL) in DCM (10 mL) was stirred at room temperature overnight. NaCNBH4 (0.01 g, 0.16 mmol) added and resulting solution was stirred 30 min. The crude product was purified by TLC plate to give the title compound at 50% yield. Calcd MW 595.8. Found MH+ 596.4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2c(Cl)cccc2N1
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2Cl)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 0.4 g, 0.022 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.47 g, 0.0026 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (100 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. MS (M+1): 259.9.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:26])[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To the solution of benzyl 3-(tert-butyldimethylsilyloxy)propylcarbamate (5 g, 15.5 mmol) in tetrahydrofuran (20 ml), sodium hydride (1.24 g, 31 mmol, 60% in mineral oil) and iodomethane (3.86 ml, 62 mmol) were added slowly. The reaction temperature was warmed up to room temperature, and stirred for overnight. The reaction was completed quenched by water and organic material was extracted with ether. After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAC:Hx=1:10) to give title compound (4.9 g, 94%) as light yellow oil.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22](N)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.Cl[Cu]>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]4[C:32]5[C:31]([C:30]6[C:25]([C:24](=[O:34])[C:23]=5[CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=[CH:28][CH:29]=6)=[O:33])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21

Procedure:
Following the procedure as descrilbed in Example 1, but suspending the 1-chloroanthraquinone, 1,4-diaminoanthraquinone, sodium carbonate and CuCl in 300 ml of nitrobenzene, the anthrimide is obtained in a yield corresponding to that of Example 1. When following a conventional procedure, i.e. mixing the components and heating them slowly, if such a concentrated reaction mixture is employed, the reaction can no longer be carried out in an agitator vessel.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]([C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:10]([NH:8][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1])[N:11]=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A solution of n-valeryl chloride (1.93 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.224 g) and triethylamine (1.784 g) in methylene chloride (40 ml) under ice cooling, and the stirring was continued for 30 minutes. The reaction mixture was evaporated and the resultant residue was extracted with ethyl acetate after addition of water. The extract was washed successively with 5% hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate, and then concentrated to a small volume under reduced pressure. The resultant residue was crystallized from diethyl ether, collected by filtration, washed with diethyl ether and dried to give 5-methyl-6-phenyl-3-(2-valerylhydrazino)-1,2,4-triazine (3.406 g).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:1]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=C(O)CCCCCn1cnc2cnc3ccccc3c21
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(CCCCCn1cnc2cnc3ccccc3c21)N1CCOCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
6-(1H-Imidazo[4,5-c]quinolin-1-yl)hexanoic acid (2.5 g, 8.8 mmol) was treated with oxalyl chloride (1.39 mL, 15.9 mmol) and morpholine (2.31 mL, 26.5 mmol) according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride was carried out at ambient temperature, and the reaction with morpholine was complete after one hour. Following the work-up procedure, 3.1 g of 1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline were obtained.