Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:22]#N.[Na+]>CC#N.CC(O)=O>[CH3:22][N:18]1[CH:12]2[CH2:13][O:14][CH2:15][CH:16]1[CH2:17][N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH2:11]2
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 112f (2.0g, 7.5 mmol) in MeCN (60 ml) was added HCHO (1.4 ml, 16 mmol) and 5 drops of AcOH at room temperature. Then NaCNBH3 (1 g, 16 mmol) added and the mixture was stirred for 2h. It was poured onto water and extracted with EA (100*3). The organic layer was dried over Na2SO4, filtered off, evaporated, and purified through a silica gel column eluting with PE:EA=5:1 to 1:1 to give 112g as a colorless oil (1.5g, 72%) MS: [M+H]+: 283
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg) was prepared from (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[N:30][C:29]=1[CH3:36]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[N:30][C:29]=1[CH3:36]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(C)c(C)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CCl)nc1C
Temperature: 0 °C

Procedure:
A reaction mixture containing N-chlorosuccinimide (6.67 g, 50.0 mmol), benzoylperoxide (50 mg) and TMPZ (6.81 g, 50.0 mmol), in 125 ml of reagent grade CCl4 was refluxed for 12 hours. The reaction solution was then cooled to 0° C. and filtered, removing succinimide. The solvent was evaporated in vacuo resulting in an oil (chloromethyltrimethylpyrazine). The oil was cooled to 0° C. and 25 ml of distilled n-amyl amine was dripped into the oil over a 20 minute period. The reaction mixture was stirred in an ice bath until an exothermic reaction ensured whereby the mixture was gently refluxed for 5 hours. Upon filtration of this reaction mixture, the resulting oil was chromatographed by flash column chromatography using 230-400 mesh silica gel (available from Fisher Scientific Co., King of Prussia, Pa.). Fractional separation was obtained by using a gradient solvent system (100% CHCl3 →25:1 CDCl3 /MeOH+1% NH4OH). Purification by Kugelrohr distillation at 90° C./15 mm Hg afforded 15% yield of a clear oil. m.p. 174°-175° C. Analysis: H-NMR(CDCl3) (ppm): 3.8(2H,S), 2.6-2.7(2H,t), 2.45-2.5(9H,t), 1.8-1.9(2H,m), 1.5-1.6(2H,m), 1.3-1.37(4H, sextet), 0.8-0.9(3H,t).
Reaction SMILES: C(N1[CH2:13][CH2:12][NH:11][CH2:10]C1)(OC(C)(C)C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:22]=O)=[CH:17][CH:16]=1.N1CCC1>>[N:11]1([CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:10][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Agent: C1CNC1
Product: Clc1ccc(C(CN2CCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33B but replacing bis-(4-chloro-phenyl)-acetaldehyde and N—BOC-piperazine with (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde and azetidine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.99 [M+H]+ 338.09. 1H NMR (Me-d3-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][C:42]1=[O:47]>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:44]2[CH2:45][CH2:46][NH:41][C:42](=[O:47])[CH2:43]2)=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)C=Cc2ccc(Oc3ccccc3)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.15 g (0.62 mmol) of 3-(6-phenoxy-pyridin-3-yl)-acrylic acid, 1.72 g (15 mmol) of NEM and 546 mg (1.6 mmol) of TOTU were dissolved in 5 ml of DMF and stirred at room temperature for 15 min. 163 mg (1.626 mmol) of piperazin-2-one were added and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by silica gel chromatography. Yield: 153 mg.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH:19]([NH2:21])[CH3:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH:19]([NH:21][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH3:20])([O-:16])=[O:15]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: CC(N)CO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.5 g of (4R)-2-oxothiazolidine4-carboxylic acid and 2.3 g of 1-(nitrooxymethyl)ethylamine nitrate, to obtain 0.35 g of the title compound as colorless crystals, melting at 112°-114° C. (after recrystallization from ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[K+].[Br-]>>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:13][CH:12]=1
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1cccnc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2cccnc2)cc1
Yield: 62.82 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.5 g, 83 mmol) and 4-methoxyaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (11.6 g, yield 62.82%, mp 137-139° C., purity 97.2% by HPLC). 1H-NMR (CDCl3):δ 3.81 (s, 3H), 4.94 (bs, 2H, D2O exchangeable), 6.93 (s, 4H), 7.37-7.4 (d, 1H), 8.22-8.24 (d, 1H), 8.70-8.71 (d, 1H), 9.0 (s, 1H). IR (KBr) cm−1: 3281, 3085, 3001, 2960, 2937, 1660. MS m/z:228.2 (M+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl.CC[O:17][CH2:18][CH3:19]>>[CH2:7]([C@H:9]1[CH2:10][CH2:11][C@H:19]([CH:18]=[O:17])[CH2:7][CH2:8]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOCC
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C=O)CC1

Procedure:
A solution of 59.0 g. of trans-4-n-pentylcyclohexane carbinol in 100 ml. of ether is added to a suspension of 125 g. of pyridinium chlorochromate in 900 ml. of methylene chloride and the mixture is stirred at room temperature for 2 hours. The mixture is then diluted with 400 ml. of ether, stirred for a further 15 minutes and the solution is decanted off from the tarry precipitate. The precipitate is back-washed with ether. The combined organic solutions are filtered through a Florisil column. The trans-4-n-pentylcyclohexane carboxaldehyde obtained after evaporation of the filtrate is used directly in the next step.
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.[CH3:42][C:43]1[O:47][C:46]([C:48]([F:51])([F:50])[F:49])=[C:45]([S:52](Cl)(=[O:54])=[O:53])[CH:44]=1>C(#N)C>[F:51][C:48]([F:49])([F:50])[C:46]1[O:47][C:43]([CH3:42])=[CH:44][C:45]=1[S:52]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[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])(=[O:54])=[O:53]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c(C(F)(F)F)o1
Yield: 22.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0277 g, 0.0600 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-methyl-2-trifluoromethyl-3-furansulfonyl chloride (0.0486 g, 0.195 mmol) to obtain 4-(2-trifluoromethyl-5-methyl-3-furansulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0092 g, yield 23%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]=4[CH:24]=[CH:25][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:26][C:17]4[C:16](=[CH:25][CH:24]=[C:19]5[NH:20][C:21](=[O:23])[NH:22][C:18]5=4)[O:15][CH2:14]3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2COc3ccc4[nH]c(=O)[nH]c4c3O2)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.60 g (1.6 mmole) of (8R)-1,3,7,8-tetrahydro-8-[[[(4 methylphenyl)sulfonyl]oxy]methyl]-2H-[1,4]dioxino[2,3-e]benzimidazol-2-one and 1.7 g (8.0 mmole) of 4-(4-fluorobenzoyl)piperidine in 30 mL of DMSO was heated at in 90° C. under nitrogen for 5 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give the free base as a colorless oil. This was recrystallized from ethanol with the addition of 4 N isopropanolic HCl to give 0.13 g of the (S)-enantiomer of the title compound. A second recrystallization from ethanol gave 0.095 g of the product as a white solid hydrochloride, hydrate, m.p. 250-256° C. (d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:4][CH:3]=1.Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:26]=2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)c1ccccn1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To 160 mL of an ethanol solution of 13.0 g (45.1 mmol) of (E)-3-(4-bromophenyl)-1-(2-pyridyl)-2-propen-1-one, 7.3 g (46.6 mmol) of benzamidine hydrochloride and 3.6 g (90 mmol) of sodium hydroxide were added under argon atmosphere, and the mixture was stirred for 16 h under heat refluxing. After cooling the reaction mixture to room temperature, a formed solid was collected by filtration and washed with water and methanol to obtain 4.31 g (yield: 25%) of 4-(4-bromophenyl)-2-phenyl-6-(2-pyridyl)pyrimidine as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH2:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccccc1S
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccccc2N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 2-Amino-benzenethiol (2.41 g, 19.23 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. (0.990 g, 21%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([F:13])([F:14])[F:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
2-(4-Bromo-2-(trifluoromethyl)phenoxy)ethanol (17.54 mmol, 5 g) and triethylamine (35.1 mmol, 4.88 ml, 3.55 g) were combined and stirred in DCM (100 ml) at 0° C. methanesulfonyl chloride (26.3 mmol, 2.036 ml, 3.01 g) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated in vacuo to afford 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate. (5.64 g)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1.O>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:17][CH:18]=1.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:21])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 16 h
Yield: 187.6 %

Procedure:
4-Methylbenzenesulphonyl chloride (4.38 g) was added portionwise to a solution of 3-bromobenzeneethanol [Example H(a)] (2.30 g, 11.4 mmol) in pyridine (30 ml) at 0° C., and the mixture stood at -20° C. for 16 h. The mixture was diluted with water, extracted with diethyl ether, the extracts combined, washed twice with aqueous 4N hydrochloric acid and once with saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to afford a pale yellow oil (3.98 g). [M-OTs]+ 182; 360 MHz 1H n.m.r (CDCl3) 7.66 (2H, d, J 8.3 Hz), 7.34 (1H, dm, J 7.9 Hz), 7.30-7.26 (2H, m), 7.20 (1H, d, J 1.5 Hz), 7.12 (1H, t, J 7.7 Hz), 7.05 (1H, d, J 7.7 Hz), 4.20 (2H, t, J 6.8 Hz), 2.91 (2H, t, J 6.8 Hz), 2.44 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:11]([NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccc(F)c1

Procedure:
Following a similar procedure to that described in Example (1b), 1.63 g of isomer B of N-[(R)-1-(3-fluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 2.11 g of nickel chloride hexahydrate, 6.74 g of sodium borohydride and 20 ml of methanol were reacted, to obtain 1.45 g of isomer B of the title compound as a colorless oil.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@@H:34]12>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[N:25]=[C:17]([CH2:16][N:12]3[CH2:11][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@H:34]4[CH2:13]3)[S:18][C:19]=2[N:20]=1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCN4CCC[C@H]4C3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (34 mg, 43%).
Reaction SMILES: C(S([C:8]1[N:13]=[C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:15]2)[CH:11]=[CH:10][N:9]=1)(=O)=O)CCC.C([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30](C)C)C>CN1C(=O)CCC1>[CH3:16][S:23]([N:29]([CH3:30])[CH:33]1[CH2:34][CH2:17][CH:22]([NH:14][C:8]2[N:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:21][CH2:35]1)(=[O:25])=[O:24]
Reactant: CCCCS(=O)(=O)c1nccc(-n2cc(S(N)(=O)=O)c3ccccc32)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C1CCC(Nc2nccc(-n3cc(S(N)(=O)=O)c4ccccc43)n2)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 120.6 %

Procedure:
1-(2-Butylsulfonyl-pyrimidin-4-yl)-1H-indole-3-sulfonic acid amide (250 mg, 0.634 mmol), trans-(N-methyl-N-methylsulfonyl)cyclohexyldiamine acetate (422 mg, 1.584 mmol) and N-ethyl-diisopropylamine (205 mg, 1.584 mmol) were combined in a microwave vial, NMP added under N2, and the vial capped and stirred for 5 min at RT. The vial was then heated to 170° C. in a microwave reactor for 2.5 h, and left to stand at RT overnight. The mixture was then poured into ice water, and the resulting light yellow solid filtered, washed with water (30 mL) and Et2O (40 mL) and air-dried. The crude product was recrystallized from EtOAc-CHCl3 to provide 1-{2-[4-(methanesulfonyl-methyl-amino)-cyclohexylamino]-pyrimdin-4-yl}-1H-indole-3-sulfonic acid amide (183 mg, 60% yield) as a light yellow solid (Compound 321).
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:24]1[N:23]=[C:22]2[CH:26]=[N:27][CH:28]=[CH:29][C:21]2=[N:20][C:19]=1[N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[F:2])[CH2:11][CH2:10]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (144 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (260 μL, 1.500 mmol) in DCM (1.0 mL) was stirred at room temperature for 30 min. The mixture was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in EtOAc and filtered through a silica pad. The filtrate was concentrated to afford the crude title compound (200.7 mg, 100%) as a yellow oil, which was used without further purification. ESI-MS m/z [M+F]+ 389.2.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([NH:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][NH:43][CH2:44][CH3:45])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCNC(=O)CCl
Product: CCNCCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 21.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-ethylacetamide (11 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (5.0 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][C@@H:28]([CH3:31])[CH2:27][NH:26]1.N[C@H](C(N[C@H](C(O)=O)C)=O)C.O=C1NCCNC1=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH2:27][C@H:28]([CH3:31])[NH:29][CH2:30][C@@H:25]2[CH3:24])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Agent: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: O=C1NCCNC1=O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Yield: 39 %

Procedure:
The crude benzhydryl chloride (approx. 42 mmol) was combined with 9.55 g (84 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine, prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described in J. Org. Chem. 50: 4909-13 (1985), and 30 mL of toluene and heated at reflux overnight under nitrogen. The toluene was removed under vacuum, and the residue was redissolved in diethyl ether and washed with 1.0 M sodium hydroxide followed by saturated aqueous sodium chloride. The ether solution was dried over sodium sulfate and the solvent removed to give a dark oil. The product was purified by chromatography on silica gel (Waters Prep 500) with 0.5-0.7% ethanol in dichloromethane with 0.1% triethylamine to give 8.01 g (39%) of (2S,5S)-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers.