Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:29][N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([C:11]2[C:12]3[C:13]([C:31]4[N:30]([CH3:29])[CH:34]=[CH:33][CH:32]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[O:28])=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: Cn1cccc1-c1cc(F)cc2c1c(C(=O)c1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (see Example 69) and 1-methyl-2-(tributylstannyl)-1H-pyrrole, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[C:4]=1[CH3:13].C(OC(=O)C)(=[O:16])C>>[OH:16][CH2:12][C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: COc1c[n+]([O-])c(C)c(C)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cnc(CO)c(C)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4.5 of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are warmed to 110° C. in 20 ml of acetic anhydride in the course of 30 minutes and the mixture is then concentrated on a rotary evaporator. The oily residue, which consists of the intemediate 2-acetoxymethyl-4,5-dimethoxy-3-methylpyridine, is stirred in 30 ml of 3N sodium hydroxide solution at 80° C. for 2 hours, the mixture is extracted, after cooling, five times with 30 ml of methylene chloride each time, the combined organic phases are washed twice with 2N sodium hydroxide solution, dried and concentrated and the residue is stirred with petroleum ether, filtered off with suction and dried. 4.0 g (89% of theory) of 2-hydroxymethyl-4,5-dimethoxy-3-methylpyridine of m.p. 91°-92° C. are obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[C:14]=4[F:30])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)n(C)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CC(=O)N[C@@H](C)COc1nn(C)c(-c2nc3ccc(OCC4CC4)cc3o2)c1F
Temperature: 60 °C
Reaction time: 7 h
Yield: 5.5 %

Procedure:
A mixture of N-[(1S)-2-({5-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-1-methyl-1H-pyrazol-3-yl}oxy)-1-methylethyl]acetamide (193 mg), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (427 mg) and acetonitrile (10 mL) was stirred at 60° C. for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (11.2 mg).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]([O:18]C)=O)[CH:15]=2)[N:9]=1)[NH2:3].[NH3:20]>O1CCCC1>[C:16]([C:14]1[CH:15]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:11]=[N:12][CH:13]=1)(=[O:18])[NH2:20]
Reactant: N
Reactant: COC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Solvent: C1CCOC1
Product: NC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3-yl)thiazole (500 mg) in 28% ammonia solution (15 ml) and tetrahydrofuran (15 ml) was stirred at room temperature for 9.5 hours. The solvent was removed under reduced pressure. The residue was washed with methanol to afford 4-(5-carbamoylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole (350 mg).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:12][C:10]2[S:11][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:9]=2)=[O:30])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccc(F)cc2)cc1
Yield: 85.9 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-fluoro-benzyl)-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 13 and p-cyanobenzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography, and recrystallized with petroleum ether and ethyl acetate to obtain a product as a white solid in a yield of 85.9%, mp: 191-192 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.79 (3H, s, OCH3), 4.18 (2H, s, CH2), 6.73 (2H, d, J=8.96 Hz, ArH), 7.03 (2H, t, 3JFH=3JHH=8.68 Hz, ArH), 7.19 (2H, dd, 3JHH=8.96, 4JFH=5.60 Hz, ArH), 7.24 (2H, d, J=8.96 Hz, ArH), 7.53 (2H, d, J=8.40 Hz, ArH), 7.76 (2H, d, J=8.40 Hz, ArH), 11.74 (1H, br, CONH); EI-MS m/e (%): 443.1 (M, 100), 130.0 (48); HREI-MS Calcd. for C25H18FN3O2S: 443.1104. found: 443.1108. Anal. Calcd. for C25H18FN3O2S: C, 67.71; H, 4.09; N, 9.47. found: C, 67.89; H, 3.97; N, 9.42.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2>N1C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][CH:19]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2
Reactant: Cc1cc(-c2ccc(N)cc2)cc2ccc(=O)[nH]c12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc(NS(C)(=O)=O)cc2)cc2ccc(=O)[nH]c12

Procedure:
Methanesulphonyl chloride (0.15 cm3) was added dropwise to a stirred solution of 8-methyl-6-(4-aminophenyl)-2-(1H)-quinolone (0.47 g) (see Example 13) in pyridine (3 cm3) at room temperature. After 0.5 hours volatile material was removed in in vacuo and the residue was partitioned between water (50 cm3) and dichloromethane:methanol, 4:1 (50 cm3). The insoluble material was filtered off, washed with methanol (10 cm3) and dried to afford the title compound, m.p. 340°-343° (0.45 g).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].Br>C(OCCCC)CCC>[C:8]1([C:4]2[C:3](=[O:14])[CH2:2][CH2:7][CH2:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Agent: Br
Solvent: CCCCOCCCC
Product: O=C1CCCC=C1c1ccccc1
Yield: 79.7 %

Procedure:
A suspension of 4.97 g (19.6 mmole) of 2-bromo-6-phenylcyclohexanone in 120 mL of di-n-butyl ether was heated at 175° C. for 7 hours, at which point evolution of gaseous HBr had essentially ceased. The mixture was concentrated in vacuo and the residue purified by flash chromatography with 75:25 methylene chloride: hexanes to provide 2.69 g (80%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][OH:23])[N:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][O:23][CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CO)ccc1C(=O)c1ccc2c(c1)OCO2
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(COCOCC[Si](C)(C)C)ccc1C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a dichloromethane(9 ml) solution of 6-hydroxymethyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.71 g,4.50 mmol) were added ethyldiisopropylamine(3.9 ml) and 2-trimethylsilylethoxymethyl chloride(2.4 ml) at room temperature. The mixture was stirred at room temperature for 17 h, partitioned between AcOEt and water, The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by MPLC(E. Merck lobar column Kieselgel 60/hexane:AcOEt=3:1 to 1:1) to give 6-(2-trimethylsilylethoxymethoxymethyl)-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-carboxylic acid methyl ester(1.44 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[NH3:16]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:16])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Br)c2cnc(S(C)(=O)=O)nc21
Reactant: N
Solvent: C1COCCO1
Product: Cn1nc(Br)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (WO 2003029209, page 46) (0.215 g, 0.0074 mol) is dissolved in 0.5M ammonia in 1,4-dioxane (11 ml) and stirred overnight at room temperature. The reaction mixture is concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH3:32])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH3:32])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-methoxybenzyl (S)-(+)-2-(N-CBz-L-valyloxy)propionate (14.0 g, 31.5 mmole) in dichloromethane (50 ml) was added trifluoroacetic acid (25 ml) and the solution was stirred for five hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 9.4 g=92%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25]([OH:27])=O)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:25](=[O:27])[C:24]2[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:20])=[O:21])[CH:23]=2)=[C:4]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1-c1cc(F)ccc1C
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [6-chloro-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (5%). MS (ESI): m/z=501.07 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2>C1C=CC=CC=1.CCO.O.[OH-].[K+]>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
Ethyl 5-(9-oxoxanthen-2-oxy)valerate (8.0 g, 24 mmol) prepared as described above was dissolved in a mixture of benzene (10 mL), 95% EtOH (40 mL), and water (5 mL), and 4N aqueous KOH (8 mL) was added. The mixture was refluxed for 6 hours (reaction complete by TLC), and partially concentrated (final volume ~10 mL). Absolute EtOH (10 mL) was added, and the resulting white precipitate was collected and washed with EtOH (2×10 mL). Yield: 1.7 g (21%), of potassium salt. The filtrate was evaporated, and the residue was dissolved in water (100 mL). The aqueous solution was extracted with EtOAc (3×20 mL), and the aqueous phase was added dropwise to a mixture of ice-water (100 mL) and 12N aqueous HCl (15 mL). A light-gray precipitate formed, which was collected, washed with water (3×10 mL), and dried. Yield: 5.45 g (74%) of free acid. A small amount of the product was recrystallized from n-hexane-EtOH (10:1) for elemental analysis. Fine white needles.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:13]([N:15]([CH:17]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:18][C:19](O)=[O:20])[CH3:16])=[O:14].[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([CH3:50])[CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:19](=[O:20])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]2[CH:11]=[C:10]([C:9]([F:41])([F:8])[F:40])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[CH3:16])[CH2:22][C:23]2[CH:24]=[CH:25][C:30]3[C:31](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:32]=2)=[C:45]([CH3:50])[CH:44]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1NC(=O)CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 0.055 ml (0.393 mmol) of triethylamine and 38 mg (0.0786 mmol) of 3-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-4-(2-naphthyl)-butanoic acid in 0.5 ml of methylene chloride and a solution of 33.3 mg of 1-propanephosphonic acid anhydride in 0.4 ml of methylene chloride are added in succession to 10.3 mg (0.0943 mmol) of 4-chloro-2-methylaniline and the mixture is left to stand at room temperature overnight (>16 hours). The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The aqueous phase is extracted with a further 0.8 ml of methylene chloride. The combined organic phases are concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/acetone (7:3) Rf =0.48.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6](Cl)[C:7](=[O:13])[NH:8]2.O.[PH2]([O-])=O.[Na+]>[Pd].O>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2
Reactant: O=C1Nc2cccc(CCBr)c2C1Cl
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: O=C1Cc2c(CCBr)cccc2N1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
4-(2'-Bromoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one (23.6 g. 86 mmol), sodium hypophosphite hydrate (35 g) and 10% palladium/carbon (60% w/w wet, 2.6 g) were stirred in industrial methylated spirit (250 ml)/water (30 ml) at 80° C. The reaction was complete after 2 hours as monitored by HPLC. Inorganic components were removed by filtration and the organic solvent was removed in vaccuo. The solid residue was slurried in water (100 ml) and dried overnight to give 17.0 g (82%) of 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][NH2:11])=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=O)[CH:3]=1.C(O)C>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][N:11]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:4]=2[CH:3]=1
Reactant: NCC(=O)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CN=C(c2ccccc2F)c2cc(Br)ccc2N1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
A round-bottomed flask was charged with N1-{4-bromo-2-[(2-fluorophenyl)carbonyl]-phenyl}glycinamide (135 mg), ethanol (3 mL) and acetic acid (0.5 mL). The mixture was heated to reflux for 15 min, then cooled and concentrated to dryness. The residue was treated with a saturated solution of sodium bicarbonate and stirred for 10 min. before extracting with ethyl acetate. The combined organics were dried over magnesium sulfate then filtered and concentrated to dryness. The residue was reconcentrated from diethyl ether to provide 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (100 mg) as a light yellow foam. H1 NMR (d6-dmso): 10.74 (br s, 1H), 7.71 (dd, 1H), 7.52-7.59 (m, 2H), 7.15-7.34 (m, 4H), 4.20 (s, 2H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](Cl)[N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[N:7]=[C:8]([N:3]([CH3:4])[CH3:2])[CH:9]=[C:10]([Cl:12])[N:11]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1cc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Dimethylamine hydrochloride (35.6 g, 0.44 mol) was added to a vigorous stirring solution of 2,4,6-trichloropyrimidine (80.0g, 0.44 mol) in CH2Cl2 (1.5 L) at −78° C. Triethylehtylmine (88.2 g, 0.87 mol) was added dropwise to the above mixture and stirred for 3 hours at −78° C. The resulting mixture was brought to 0° C. over a period of 3 hours and the reaction was then quenched with water (250 mL). The organic layer was separated, washed with aqueous citric acid (2×100 mL), brine (2×200 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography [eluent: EtOAc/hexanes (1:9)], giving the desired product (59.9 g, 60%).
Reaction SMILES: N.O1CCOCC1.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18](O)=[O:19])[CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]1.C1C=CC2N(O)N=[N:35]C=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.CCOC(C)=O>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18]([NH2:35])=[O:19])[CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 186.6 %

Procedure:
A solution of 0.5 M NH3 in dioxane (12 mL, 6 mmol) was added to a mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylic acid (1.1 g, 2.96 mmol), HOBt (0.455 g, 2.96 mmol), and EDC.HCl (1.54 g, 8.02 mmol) in DMF (4 mL) in a Biotage microwave vial. The vial was sealed, and the reaction was heated at 100° C. for 20 min on regular absorbance in a Biotage Initiator microwave. EtOAc (75 mL) and H2O (75 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a light yellow solid. The solid was washed with DCM (1×25 mL) to and aspirated dry to give 2.05 g (96%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][O:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:18])[CH3:19])[CH:7]=[C:8]([CH2:11][O:12][CH3:13])[C:9]=1[O:10][CH2:22][C:23]#[N:24]
Reactant: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1O
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1OCC#N
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
3-Chloro-4-hydroxy-5-methoxymethylaniline (52.8 g) and N,N-diethylaniline (42.0 g) were dissolved in ethyl acetate (300 ml). To the resultant solution was dropwise added isopropyl chloroformate (34.6 g) in 15 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water. The organic layer was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g). Sodium hydride (9.60 g, 60% dispersion in mineral oil) was added to dimethylformamide (240 ml). To the resultant mixture was added isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and chloroacetonitrile (19.0 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-cyanomethoxy-5-methoxymethylphenyl)carbamate (Compound No. 5) (67.5 g) in a yield of 76.8%. M.P., 58.5°-60.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: NCc1ccccc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2Cl)c1

Procedure:
25.5 g of 4'-chloro-3'-chlorosulfonylacetophenone were reacted with 16 g of o-chloro-benzyl amine and 25.5 g of triethyl amine and worked up. Colorless crystals from isopropanol (active charcoal), melting point: 102° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:12][CH2:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1
Reactant: CCCN1CCC(C(N)=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN1CCC(CN)CC1
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
A mixture of 1-propylpiperidine-4-carboxamide (1.2 g, 7.06 mmol) in 50 mL THF was treated in one portion with LAH (0.98 g, 14.2 mmol). The mixture was heated at reflux for 2 hours. On cooling the excess LAH was decomposed by the stepwise addition of H2O, 1N NaOH, H2O and Na2SO4 (v/v/v/w-1;1;3;12.5 based on 1 gram of LAH). After stirring for 10 min the solids were filtered and washed with EtOAc. The solvent was removed (rotovap) to give 0.9 g of title compound as a yellow oil.