Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]([C:13]1[CH:31]=[C:16]2[C:17]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[N:15]2[N:14]=1)[CH3:12]>C(Cl)(Cl)Cl>[F:7][CH:11]([C:13]1[CH:31]=[C:16]2[C:17]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[N:15]2[N:14]=1)[CH3:12]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)O)nn12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)F)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
DAST (51.2 mg) was added dropwise to a solution of the compound of Example 238 (80.0 mg) in chloroform (10 mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution and the reaction mixture was extracted with chloroform (30 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the title compound as a pale yellow powder (30.6 mg).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1cc(F)ccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Temperature: 2 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
5′-Amino-4,2′-difluorobiphenyl-2-carbonitrile (23 g, 100 mmol) was dissolved in hot 1,4-dioxane (20 ml) then treated with a chilled (5° C.) solution of hydrobromic acid (200 ml of a 48% solution in water). The resulting suspension was cooled to 2° C. (internal temperature) before adding a solution of sodium nitrite (6.9 g, 100 mmol) in water (14 ml) at such a rate that the internal temperature did not exceed 4° C. Once addition was complete the reaction was stirred at <4° C. for 1 h before pouring the reaction into a cooled (5° C.) solution of copper(I) bromide (21.5 g, 150 mmol) in 48% aqueous hydrobromic acid (75 ml). The resulting dark mixture was left to stir at ambient temperature for 15 min then heated at 50° C. for 40 min. After cooling to ambient temperature the mixture was diluted with water (1 l) and then extracted with ethyl acetate (2×400 ml). The organics were combined then washed with 10% ammonium hydroxide (500 ml), water (500 ml), brine (400 ml) and dried (MgSO4). Filtration and evaporation to dryness gave a brown oil, which crystallised on standing. Purification of this residue by dry flash chromatography (silica gel, 2-4% EtOAc/isohexane) furnished 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile as a white solid (27.5 g, 94%): 1H NMR (360 MHz, CDCl3) δ 7.11 (1H, dd, J 9, 9 Hz), 7.37-7.58 (5H, m).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[N:35][C:30]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Brc1ncccn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromo-pyrimidine
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.CO>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-[4-(trifluoromethyl)benzyl]-1H-indole-7-carboxylate (11.7 g, 35.1 mmol) was dissolved in 350 ml of 1:1 THF/MeOH and 175 ml of 2N KOH (10 eq, 351 mmol). The mixture was stirred at RT for 18 hr. Then the solvents were evaporated under reduced pressure. 2N HCl was added (pH=3) and the aqueous phase was extracted 3× with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and then concentrated under reduced pressure. 1H NMR (500 MHz, DMSO-d6): δ 12.85 (bs, 1H), 7.80 (d, 1H), 7.60 (m, 3H), 7.50 (m, 1H), 7.10 (t, 1H), 7.00 (d, 2H), 6.70 (d, 1H), 5.80 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.Cl>CO>[C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:12]1[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CO
Product: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.2 %

Procedure:
To a stirred solution of 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01) (350 mg, 0.776 mmol) in methanol (6 mL) was added concentrated HCl (3 mL) and the reaction mixture was stirred for 5 h at room temperature. After completion of the reaction, the volume of the reaction mixture was reduced by evaporation and the resultant mixture was basified with saturated aqueous NaHCO3 solution. The mixture was extracted with 10% methanol in dichloromethane, the separated organic part was dried over sodium sulfate and concentrated to get a crude product, which was purified by prep-HPLC (ammonium acetate-methanol) to afford 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01) (68 mg, 24.25%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:15])([F:14])[C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.CCN(C(C)C)C(C)C>CO>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH:24][C:9](=[O:11])[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([F:14])[F:15])=[N:21][CH:22]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(Cl)nn1
Reactant: NNc1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NNc1ccc(Br)cn1)C(F)(F)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetate (10.8 g, 45.6 mmol) and 5-bromo-2-hydrazinylpyridine (8.58 g, 45.6 mmol) in anhydrous MeOH (100 mL) was added DIEA (5.90 g, 45.6 mmol). The reaction was stirred at ambient temperature for 18 hrs. The solvent was removed via rotary evaporation and the resulting material was reconstituted in EtOAc. The organic phase was washed with water and concentrated to dryness. The resulting residue was purified by MPLC (EtOAc) to provide the title compound, N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)-2,2-difluoroacetohydrazide 45E (13.3 g, 35.1 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (d, J=8.84 Hz, 1 H) 7.11 (d, J=9.35 Hz, 1 H) 7.47-7.60 (m, 2 H) 8.06 (d, J=2.53 Hz, 1 H). ESI-MS:m/z 377.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:46][CH2:45][CH2:44][C:43]3=[O:47])=[N:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:47]=[C:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Reactant: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(-c2ccc(N3CCCC3=O)nc2)cn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)picolinamide 72-1 (22 mg, 0.05 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one 72-2 (29 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (21 mg, 0.1 mmol) in dioxane (0.5 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was redistributed between ethyl acetate and water. The organic phase was dried over Na2SO4 and concentrated with rotavap. The residue was subjected to preparative reverse phase HPLC separation to give 6′-(2-oxopyrrolidin-1-yl)-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-[3,3′-bipyridine]-6-carboxamide 72 as a solid. MS m/z 519.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.83 (d, 1H), 8.79 (d, 1H), 8.76 (dd, 1H), 8.62 (dd, 1H), 8.57 (dd, 1H), 8.52 (t, 1H), 8.34-8.29 (m, 2H), 8.10-8.02 (m, 2H), 7.96-7.88 (m, 2H), 7.84 (d, 1H), 4.79 (d, 2H), 4.16 (t, 2H), 2.71 (t, 2H), 2.18 (t, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:27]=[N:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Oc1ccc(F)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CC(C)(C)CN(CCOc1ccc(F)nc1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 60 h

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 6-fluoro-3-pyridinol (Example 51A) with the following exceptions: additional portions of ADDP and PBu3 (0.5 equiv ea) were added to the reaction mixture after 1 h, the reaction was stirred for 60 h, and the title compound was purified by flash chromatography (EtOAc/hexanes) followed by RP-HPLC (MeCN/H2O+0.1% TFA): MS (ESI) m/z 396 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[N:11][C:12]=2[CH:18]=1)=[O:21]
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: CN
Product: CNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1

Procedure:
Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 71.8 μl of a methylamine solution (2M in tetrahydrofuran), 14.8 mg of expected product are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:36]=[CH:35][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40]/[N:39]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:35][CH:36]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCC(CC(=O)O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCC(CC(=O)O)CC2)cc1

Procedure:
In analogy to example 151, step 3, (1-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoyl}-piperidin-4-yl)-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=514.4 [M−H]−.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C)C=O>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous dimethylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5 N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3)δ4.1(m,2), δ3.68(S,3), δ3.03(dd,1,J=4.3,2.7 ), δ2.8(ABq,2), δ1.17(d,3,J=6.6), δ0.98(s,9), δ0.89(s,9), δ0.23(s,6), δ0.1(s,6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.O.[C:20](OCC)(=O)[CH3:21]>C(O)C>[CH2:20]([O:12][C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][N:6]=1)=[O:13])[CH3:21]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
3 g of 5-bromo-1H-indazole-3-carboxylic acid was dissolved in 60 mL of ethanol, added with 0.6 mL of concentrated sulfuric acid, and heated under reflux for 8 hours. After allowing to cool to room temperature, addition of water and extraction with ethyl acetate were conducted, and the resultant organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated, to afford 2.7 g of the title compound as yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccsc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccsc1

Procedure:
The 2-(3-thienyl)ethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: CCc1ccncc1
Reactant: Fc1ccc(CCBr)cc1
Product: CC(CCc1ccc(F)cc1)c1ccncc1
Yield: 77.9 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.90 g (9.35 mmol) of 4-fluorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.67 g of the desired compound (yield: 77.9%). The resulting compound was identified as 1-(4-fluorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 5) by the following analytical results.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][NH:58][CH2:59][C:60]1[CH:75]=[CH:74][C:63]([CH2:64][N:65]2[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:73])[CH3:72])[CH2:66]2)=[CH:62][CH:61]=1>C(Cl)Cl>[C:71]([NH:70][CH:67]1[CH2:68][CH2:69][N:65]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([CH2:59][N:58]([CH3:57])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:75][CH:74]=2)[CH2:66]1)(=[O:73])[CH3:72]
Reactant: CNCc1ccc(CN2CCC(NC(C)=O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(NC(C)=O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (80 mg, 0.22 mmol), EDCI (61 mg, 0.32 mmol), HOBt (45 mg, 0.34 mmol), DIPEA (0.08 mL, 0.45 mmol), N-(1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-yl)acetamide dihydrochloride (36 mg, 0.13 mmol) and DCM (20 mL).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[C:30](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:28][CH:27]=2.C(N(CC)CC)C>O1CCOCC1>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[CH:32]=[C:24]([CH3:23])[NH:25]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Reactant: Cc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc2c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)cccc2[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
A mixture of 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.307 mmol), trifluoro-methanesulfonic acid 2-methyl-1H-indol-4-yl ester (129 mg, 0.462 mmol), tetrakistriphenylphosphine palladium(0) (35 mg, 30.2 μmol) and triethylamine (130 μL, 0.933 mmol) in 1,4-dioxane (1.5 ml) was heated with stirring at 100° C. for 18 hours. The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-[(E)-2-(2-methyl-1H-indol-4-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (19.3 mg, 14%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:25])([F:24])[F:26])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1

Procedure:
A solution of 3.29 g. of 1-methyl-4-(2-trifluoromethylthio-9-hydroxythioxanthen-9yl)piperidine in 15 ml. of trifluoroacetic anhydride and 30 ml. of trifluoroacetic acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness. The residue is dissolved in benzene and is washed with 10% sodium hydroxide to make the free base form. The benzene is washed with water, dried over magnesium sulfate, filtered, and the benzene is removed on a rotary evaporator. The residue is recrystallized from acetonitrile to give 1-methyl-4-[2-(trifluoromethylthio)thioxanthen-9-ylidene]piperidine, m.p. 104°-106° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH2:9][CH2:10][Cl:11]>C1C=CC=CC=1>[Cl:5][CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][CH:14]=1)[CH2:9][CH2:10][Cl:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CN(CCCl)CCCl)cc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(CN(CCCl)CCCl)cc1
Temperature: 80 °C

Procedure:
Thionyl chloride (1 ml) was added to a solution of 320 mg (1.0 mmol) of 4-[N,N-bis(2-chloroethyl)aminomethyl]benzoic acid in 2 ml of benzene, followed by stirring under heating at 80° C. for 2 hours. After the solvent was distilled out under reduced pressure, the residue was dried up under reduced pressure so that a white solid was obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][Cl:25].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Temperature: 40 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
3.5 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (12.75 mmol), 2.3 g of 1-bromo-3-chloro-propane (14.6 mmol) and 2.8 ml of triethylamine (20.1 mmol) were dissolved in 70 ml of dimethylformamide. The mixture was stirred at room temperature overnight and for further 3 h at 40° C. The reaction mixture was then extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was then purified by silica gel chromatography (dichloromethane as eluent) to yield 3.0 g (67%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH:17]=O)=[CH:11][NH:12]2>C1COCC1>[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH3:17])=[CH:11][NH:12]2
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2cccc(Br)c12
Yield: 92.2 %

Procedure:
LAH (1.0M in THF, 5.75 mL, 5.75 mmol) was added dropwise to refluxing 4-bromo-1H-indole-3-carbaldehyde (644 mg, 2.87 mmol; Intermediate 27) in dry THF (20 mL). The mixture was refluxed 1 h, allowed to attain rt. and quenched with water (220 μL), W/w 15% aq. NaOH (220 μL) and water (650 μL). The resulting precipitation was filtered off, the filtrate concentrated and the residue was extracted with aq. NaOH (10 mL) and DCM (2×10 mL). The organic layers were combined with combined with an earlier batch of this intermediate (followed this experimental and starting from 4-bromo-1H-indole-3-carbaldehyde, 100 mg, 0.45 mmol; Intermediate 27), dried and concentrated to give the title compound (556 mg, 80%) as a light brown oil. MS (ESI+) for C9H8BrN m/z 210 (M+H)+.