Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH:6]=1)[CH:33]=[O:34]
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C=O)c2)c(Cl)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of the title compound of Step B (410 mg, 1.31 mmol), hexamethylenetetramine (256 mg, 2.0 mmol) and trifluoroacetic acid (2.5 ml) under nitrogen was heated to 75° C. and stirred for about three hours. The solution was concentrated in vacuo to give a yellow viscous oil. Water (20 ml) was added to the yellow oil and the mixture was stirred for about 30 minutes at room temperature. The aqueous solution was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2×50 ml), brine (50 ml), dried, filtered and concentrated to give the title compound (440 mg ) as a crude product which was used in the next step without further purification. NMR (400 MHz, CDCl3) δ10.36 (s, 1H), 7.33 (s, 2H), 7.11-7.16 (m, 2H), 6.93 (d, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=364.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:36](OC(=O)C1C=CC(N)=CC=1F)[CH3:37]>>[CH2:36]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:34][CH3:35])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:37]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1F

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=519.0 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-fluoro-benzoic acid ethyl ester and yielded 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:18][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:30][CH2:29]4)[C:20]3=[O:31])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.CC([O-])=O.[K+]>CO.[Pd]>[CH:28]1([N:21]2[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:19]([CH2:18][C:9]3[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:15])([F:17])[F:16])[C:5]4[C:6]([N:8]=3)=[N:7][CH:2]=[CH:3][CH:4]=4)[C:20]2=[O:31])[CH2:30][CH2:29]1
Reactant: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Compound 39 (1000 mg, 2.22 mmol) was dissolved in 30 mL MeOH. Pd/C (10%) and KOAc (218 mg, 2.22 mol) were added. The mixture was placed under H2 and hydrogenated overnight. The mixture was filtrated over a plug of dicalite and evaporated. Compound 41 was purified by column chromatography on silicagel using CH2Cl2 to CH2Cl2/MeOH(NH3) 9-1 as the eluent. After evaporation 550 mg (59% yield) of 41 was obtained as a white solid with a purity of 99%. m/z=417 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.05 (m, 2H), 1.18 (s, 2H), 1.91 (s, 2H), 2.12-2.31 (m, 2H), 2.91 (tt, J=6.93, 3.48 Hz, 1H), 4.46 (t, J=7.80 Hz, 2H), 5.42 (s, 2H), 7.14 (d, J=5.27 Hz, 1H), 7.25 (dd, J=8.28, 4.77 Hz, 1H), 7.66 (dd, J=8.16, 1.38 Hz, 1H), 8.36 (d, J=5.27 Hz, 1H), 8.59 (dd, J=4.77, 1.51 Hz, 1H), 8.80 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:11])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O.O>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:6]([C:5](=[O:11])[CH2:4][CH3:3])[C:7](=[O:10])[CH2:8][CH3:9])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CCC(=O)CC(=O)CC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil, 0.17 g) was added portionwise to a stirred solution of heptane-3,5-dione (0.54 mL) in N,N-dimethylformamide (4.0 mL) at 0-10° C. The resulting mixture was stirred at 0-10° C. for 10 minutes and then a solution of 1-bromomethyl-4-methanesulfonylbenzene (1.2 g) in N,N-dimethylformamide (2.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 by volume) gave title compound as a white solid, 0.61 g.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[C:24](O)=[O:25]>>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)N(CC(F)F)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-[4-(2-fluoro-phenyl)-pyridin-3-yl]-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (44%). MS (ESI): m/z=494.09 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(OC2CCCC2)c(OC)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Reaction time: 45 h
Yield: 36.2 %

Procedure:
A solution of potassium hydroxide (4.71 g) in water (32 mL) is added to a solution of methyl 4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (7.03 g) in methanol (188 mL) and the mixture allowed to stand for 45 hours. After concentrating in vacuo the residue is dissolved in water, washed with ethyl acetate and basified to pH 5 with concentrated aqueous hydrochloric acid. The mixture is extracted with dichloromethane, the extracts dried (MgSO4) and evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.4 g) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2c(I)cccc12
Solvent: CN(C)C=O
Product: Clc1ccnc2c(I)cccc12
Yield: 97.8 %

Procedure:
8-Iodo-1H-quinolin-4-one (3.36 g, 8.72 mmol) was suspended in POCl3 (8 mL, 87.2 mmol) and catalytic anhydrous DMF (6.72 μL) was added. The mixture was refluxed for 1 h. The hot crude was poured over ice and the mixture stirred until ice was completely melted. Solid was filtered off, thoroughly washed with water and kept in the vacuum oven overnight to afford 4-chloro-8-iodo-quinoline as a grayish solid (2.47 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.45 (t, 1H), 7.81 (d, 1H), 8.19 (dd, 1H), 8.45 (dd, 1H), 8.87 (d, 1H). Exact mass calculated for C9H5ClIN 288.92, found 289.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([CH:14]([CH3:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>O1CCOCC1>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O:13][C:5]2[N:4]([CH:14]([CH3:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:3]=[C:2]([CH3:1])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: Cc1[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c(=O)c1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2ccc(Cl)c(Cl)c2)c(OC(=O)c2ccc(F)cc2)c1-c1ccccc1

Procedure:
0.1 mol (34.7 g) of 3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone was dissolved in 300 ml of absolute dioxane. After adding 15 ml of triethylamine, 0.11 mol (17 g) of p-fluorobenzoyl chloride in dioxane was added dropwise. After heating for several hours under reflux, the reaction batch was worked up as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[OH:10]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Reaction time: 18 h
Yield: 107.3 %

Procedure:
To 20 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanone dissolved in 80 ml of ethanol are introduced portionwise 8.6 g of sodium borohydride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 21.63 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIa) was prepared by reacting 0.0284 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][CH2:54][CH2:55][CH2:56][N:57]([CH3:80])[CH2:58][C@@H:59]([C:68]2[CH:77]=[CH:76][C:75]([OH:78])=[C:74]3[C:69]=2[CH:70]=[CH:71][C:72](=[O:79])[NH:73]3)[O:60][Si:61]([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62])=[CH:48][CH:47]=1>>[Si:61]([O:60][C@H:59]([C:68]1[CH:77]=[CH:76][C:75]([OH:78])=[C:74]2[C:69]=1[CH:70]=[CH:71][C:72](=[O:79])[NH:73]2)[CH2:58][N:57]([CH3:80])[CH2:56][CH2:55][CH2:54][C:53]#[C:52][C:49]1[CH:50]=[CH:51][C:46]([NH:45][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:47][CH:48]=1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:62])[CH3:63]
Reactant: CN(CCCC#Cc1ccc(N)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCN(C)C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 103 in place of 8-aminooctanol. ES/MS calcd. for C54H59N6O8SSi+ 979.4. Found m/z=979.6 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Li+].CO.Cl>CCOCC>[C:23]([O:22][C:20](=[O:21])[N:18]([CH:4]([CH2:3][OH:2])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:19])([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CO)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 32.0 g (86.6 mmol) of 2-(N-tert-butoxycarbonyl-N-methyl-amino)-3,3-diphenyl-propanoic acid methyl ester in 400 ml of ether there are added in succession 3.0 g (130.0 mmol) of lithium borohydride in portions and 5.3 ml (130 mmol) of methanol dropwise (foams!). The reaction mixture is stirred under reflux for 3 hours, then cooled in an ice bath, and 40 ml of 0.5N hydrochloric acid are added (foams!). After further dilution with water, the mixture is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, yielding the title compound in the form of a white foam. TLC: methylene chloride/methanol (95:5) Rf=0.46; FAB-MS (M+H)+=342.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:23][O:24][CH2:25][C:26](O)=[O:27]>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:26](=[O:27])[CH2:25][O:24][CH3:23])=[O:7])#[N:3]
Reactant: COCC(=O)O
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: COCC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
L11. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with methoxy-acetic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2-methoxy-acetyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless foam. MS: 400.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C)C=O>O>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:5]=1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 84.9 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino) methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.0 g), ethyl chloroformate (0.72 g) and dimethylformamide (30 ml) was stirred at 25° for 12 h. The suspension was diluted with water (100 ml) and extracted with ethyl acetate. The organic extracts were evaporated to leave the title compound as a pale yellow oil (2.1 g). TLC silica, methanol/0.88 amonia 80:1, Rf 0.61. NMR (D2O 2.52 t (1H); 2.8-3 m (3H); 5.42 s (2H); 5.6-6 m (6H); 6.48 t (2H); 6.5 s (3H); 7.09 s (6H); 7.88 m (2H); 8.67 t (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)=[O:42]>ClCCl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([O:43][C:41](=[O:42])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[CH2:15][CH3:16])=[CH:45][CH:46]=1
Reactant: CCN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of rac-[(3R,4S)-3-(3,4-dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (25 mg, 0.06 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (10 uL, 0.06 mmol). It was cooled to 0° C. and 4-fluorophenyl chloroformate (8 uL, 0.06 mmol) was added and the reaction mixture was stirred for 30 min at this temperature and then 2 h at ambient temperature. Concentration and purification by chromatography (SiO2, ethyl acetate) afforded the title compound (17 mg, 52%) as a colorless foam. MS m/e: 590.4 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH2:25][NH:26][CH2:27][CH2:28][CH3:29].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([S:8][C:9]3[CH:10]=[C:11]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:4]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(Sc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N

Procedure:
A mixture of N-[3-(4-Amino-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0016 mol) and cyanogen bromide (0.0020 mol) in ethanol (q.s.) was reacted overnight at room temperature and then the organic solvent (EtOH) was evaporated. The obtained concentrate was warmed in EtOH and then cooled. The mixture was filtered and the collected residue was recrystallized from EtOH to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[N:10]([CH2:24][CH2:25][CH2:26][Cl:27])[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Cl)n(CCCCl)c(=O)n1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a suspension of 18.93 g (80 mmol) of 3-benzyl-6-chloropyrimidine-2,4(1H,3H)-dione and 17.69 g (128 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 15.8 ml (160 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 13.46 g (53.7%, light yellow powder) of the desired product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[NH:49]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[N:49]1([C:30]([C:29]2[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCCCCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and azepane and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C21H21BrN4O3S, 488.0; m/z found, 487/489 [M−H]−. HPLC (reverse phase): RT=9.34 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.08 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.87 (br s, 1H), 8.50 (d, J=7.3 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.1, 1.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 3.33-3.28 (br m, 2H), 2.93-2.91 (m, 2H), 1.68-1.65 (m, 2H), 1.58-1.52 (m, 2H), 1.50-1.42 (br m, 4H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=[O:21]>CN1C(=O)CCC1>[CH2:1]([O:8][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
To benzyl alcohol (1.1 g, 10 mmol) in NMP (20 mL) was added sodium hydride (60% in mineral oil; 0.44 g, 11 mmol), and the mixture was stirred for 30 minutes at room temperature. The mixture was then added to a vial containing 2-chloro-5-fluorophenylacetic acid (1 g, 4.5 mmol), and the reaction was stirred at 120° C. for 3 hours. Acidic work-up gave the desired product (1.8 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:8])=[O:7]
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
Thiophene-2-sulfonyl chloride (10 g, 54 mmol) was dissolved in dichloromethane (15 mL) and added dropwise to a round-bottom flask containing a solution of piperidine (10.6 mL, 108 mmol) and diisopropylethyilamine (18.8 mL, 108 mmol) in dichloromethane at 0° C. The reaction was stirred at 0° C. for 15 min and then allowed to warm up to room temperature. After 2 h, the reaction was washed successively with a saturated solution of sodium bicarbonate, water, 1 N HCl and a saturated solution of sodium chloride. The organic layer was dried with sodium sulfate, concentrated and placed on a vacuum line to give an off-white solid (11.98 g). MS (M+H)+ 232.