Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]1([N:34]([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:28]1([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:48]=[CH:47][C:44]([CH:45]=[CH2:2])=[CH:43][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a two necked flask, under argon atmosphere, 22.18 g (54.87 mmol) of methyl(triphenyl)phosphonium iodide are dissolved in 100 mL of freshly distilled tetrahydrofuran (THF). After the mixture is cooled to the temperature of 0° C., 1.5 eq. (6.16 g) of potassium tert-butoxide are incorporated. After 30 min of stirring at 0° C., a solution of 4-(N,N-diphenylamino)-benzaldehyde (10 g, 36.80 mmol) in 30 mL of THF is added to the mixture, drop by drop. The temperature of the medium is then left to return to ambient temperature and the stirring continued for 4 additional hours. The medium is then hydrolysed with a saturated sodium carbonate solution then extracted in dichloromethane. The organic phase is washed successively with water, a saturated NaCl solution then dried on Na2SO4. After filtration and evaporation, the crude product is purified on chromatography column on silica [eluent—hexane/ethyl ether: 80/20].
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]2[S:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[CH2:13][C:14]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Fc1ccc2c(c1)C(N1CCNCC1)Cc1cc(Cl)ccc1S2

Procedure:
24.5 G. of 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine, 350 ml. of ethyleneglycol, 19 g. of potassium hydroxide and 1.5 ml. of water are heated together at 160° for 1 hours. The reaction mixture is poured over water and extracted with chloroform. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo-[b,f]thiepin-10-yl)-piperazine as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:37]([OH:40])[C:38]#[CH:39]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:39]#[C:38][CH2:37][OH:40])[CH:17]=3)[N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reaction time: 8 h

Procedure:
To a dry flask under an atmosphere of argon gas containing 0.23 g of tert-butyl 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-iodo-4-oxo-1(4H)-quinolinyl]acetate from Preparation No. 26, 0.01 g of copper (I) iodide and 0.03 g of dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (2.0 mL) and propargyl alcohol (0.03 mL). After 1 hour the reaction is diluted with DMF (1.0 mL) and left to stir overnight. The reaction is concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol, and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 4% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0.13 g of the title compound as a solid.
Reaction SMILES: [Cl:1]C1C=CC=C(Cl)C=1CC#N.[OH-].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C(Cl)=O>C(O)C.C1C=CC=CC=1.CN(C)C=O.O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][C:23]([Cl:1])=[O:25]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A solution of (2,6-dichloro-phenyl)-acetonitrile (Intermediate A1) (commercially available at Aldrich) (18.6 g, 100 mmol) in ethanol (40 mL) and water (50 mL) was treated with KOH (30 g) and the mixture was heated to 80° C. for 20 h. The mixture was quenched with HCl until pH 3. The product was extracted with chloroform (5×50 mL). The extracts were combined, dried over MgSO4, filtered and evaporated to dryness. The product was (2,6-dichloro-phenyl)-acetic acid, 17 g (83%). A solution of (2,6-dichloro-phenyl)-acetic acid (10 g, 49 mmol) in benzene (200 mL) was treated with oxalyl chloride (32 mL, 2M in dichloromethane) followed by a few drops of dimethyl formamide. The mixture was allowed to stir for 3.5 h at rt. The solvent was removed under vacuum to give ˜11.5 g of (2,6-dichloro-phenyl)-acetyl chloride (Intermediate A2).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:24]1[CH2:21][CH2:23][CH2:29][CH2:27]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCC3)nc2c1C#N
Yield: 96.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.13 g, 0.45 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (92.0 μl, 0.54 mmol) and pyrrolidine (41.0 μl, 0.50 mmol) were added. This was heated under reflux for 4 hours, and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale yellow oil (0.14 g, 98%).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([C:17]3[N:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: Cc1cc2c(C)noc2cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2c(C)noc2cc1-c1cnc(N)cn1
Temperature: 85 °C
Yield: 26 %

Procedure:
A mixture of 6-bromo-3,5-dimethylbenz[d]isoxazole (104) (54 mg, 0.24 mmol), 2-aminopyrazine-5-boronic acid pinacol ester (14) (79 mg, 0.358 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (25 mg, 10% mol) and K3PO4 (76 mg) in 1 ml ACN, 1 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 3 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(3,5-dimethylbenz[d]isoxazol-6-yl)pyrazine-2-ylamine (109) (15 mg, yield: 26.1%, purity>95%) as light yellow solid.
Reaction SMILES: ClC1C=CC(O[C@@H](C)C(OC)=O)=CC=1CN1C2C(=CC(C(O)=O)=CC=2)C(C)=C1C.[Cl:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45]([O:47]CC=C)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:51])=[C:37]2[CH3:52])=[CH:33][C:32]=1[O:55][C@@H:56]([CH3:61])[C:57]([O:59][CH3:60])=[O:58]>>[Cl:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45]([OH:47])=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:51])=[C:37]2[CH3:52])=[CH:33][C:32]=1[O:55][C@@H:56]([CH3:61])[C:57]([O:59][CH3:60])=[O:58]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(Cl)c(O[C@@H](C)C(=O)OC)c1
Agent: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same general protocol as described for the synthesis of the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (Step 4, Example 26), using the (S)-allyl 1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate instead of the (S)-allyl 1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]>O1CCOCC1.[Pd]>[C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(/C=C/C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCc1c(OCC(O)COc2ccc3c(=O)cc(CCC(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 65.6 %

Procedure:
trans-Ethyl 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propyl phenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]acrylate (1.2 g) in dioxan was hydrogenated, over a palladium-charcoal catalyst, at atmospheric pressure and ambient temperature. The catalyst was removed by filtration and the concentrated filtrate chromatographed over silica-gel (60 g). Elution with ether afforded a white solid which was crystallised from etherpetrol (40°-60°) to yield ethyl 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]propionate (0.79 g), mp 137°-138° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1>CC(C)=O>[CH2:1]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Yield: 93.2 %

Procedure:
To a solution of docosyl bromide (25 g, 0.064 mol), potassium carbonate (9.0 g) and sodium iodide (9.6 g) in acetone (150 ml), ethyl p-hydroxybenzoate (10.2 g, 0.061 mol) was added, and then reacted for 12 h under reflux with stirring. After cooling, the reaction mixture was filtered to remove inorganic materials, taken up in H2O (500 ml), and extracted with CH2Cl2 (3×100 ml). The organic layer was separated, washed with H2O, dried over MgSO4, and evaporated to dryness. The resultant residue was recrystallized from ethyl acetate to give ethyl 4-docosyloxybenzoate (27 g) as a white crystals; mp 56.5°-59.5° C. Then ethyl 4-docosyloxybenzoate (27 g) was stirred in H2O (120 ml) and ethanol (150 ml) containing sodium hydroxide (4.6 g) for 6 h under reflux. After cooling, the reaction mixture was acidified with hydrochloric acid, the resultant precipitate was filteted, washed with H2O and recrystallized from acetic acid to give the title compound as a white needles; yield: 18.5 g (72.7%); mp 99.0°-101.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:4]=2)=[CH:17][CH:18]=1)=[O:27]
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (384 mg) was dissolved in DCM (12 mL) and triethylamine (0.216 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.121 mL) and the reaction was stirred for 15 minutes at RT before being concentrated in vacuo to give the desired material.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.38) (0.405 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as light brown foam (0.41 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH2:34][NH:35][C:36]([CH:38]4[CH2:42][C:41]5([CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]5)[CH2:40][N:39]4[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:67]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][CH:6]([CH3:8])[C@H:5]([NH:4][C:3](=[O:62])[O:2][CH3:1])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[N:67]=[C:36]([CH:38]5[CH2:42][C:41]6([CH2:43][CH2:44][S:45](=[O:49])(=[O:48])[CH2:46][CH2:47]6)[CH2:40][N:39]5[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:53])[CH3:54])[NH:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[N:20]=1)=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 37.9 %

Procedure:
A solution of methyl((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8,8-dioxido-8-thia-2-azaspiro[4.5]dec-3-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (108) (107 mg, 0.12 mmol) and ammonium acetate (94 mg, 1.2 mmol) in dioxane (1.5 mL) was degassed with nitrogen and heated to 110° C. in a sealed tube for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate and filtered and concentrated in vacuo. Purified by SFC to afford the product as a tan solid (39 mg, 37% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.32 (br. s., 2H) 5.05-5.24 (m, 1H) 4.04-4.29 (m, 1H) 3.99 (br. s., 1H) 3.81 (br. s., 1H) 3.55-3.73 (m, 6H) 3.03-3.25 (m, 4H) 1.80-2.47 (m, 14H) 0.68-1.06 (m, 16H). HRMS for C44H57N8O8S (M+H)+ calc: 857.4020. found: 857.4020. Purity (LC-MS): 97%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([CH:17]=[CH:18][N:19]=2)[CH:13]=[C:14]([CH3:16])[N:15]=1>C(Cl)Cl>[Br:1][C:17]1[N:12]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:10]([Cl:9])[C:11]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2ccnc2c(Cl)n1
Solvent: ClCCl
Product: Cc1cn2c(Br)cnc2c(Cl)n1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
N-bromosuccinimide (348 mg, 1.96 mmol) is added to a solution of 8-chloro-6-methyl-imidazo[1,2-a]pyrazine (337 mg, 2.02 mmol) in DCM (6.1 mL) and the reaction is stirred at 40° C. for 10 min and then at room temperature for 1 h 30 min. The reaction mixture is diluted with DCM and washed twice with 4 mL of Na2CO3 sat., dried with MgSO4 anh., filtered and concentrated in vacuo to give 3-bromo-8-chloro-6-methyl-imidazo[1,2-a]pyrazine as a yellow solid (470 mg, 95%).
Reaction SMILES: O[CH2:2][C:3]1([S:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])=[O:7])[CH2:5][CH2:4]1.C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl>[C:12]([O:11][C:10](=[O:16])[NH:9][S:6]([C:3]1([CH2:2][F:23])[CH2:5][CH2:4]1)(=[O:8])=[O:7])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(CO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(CF)CC1
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A solution of tert-butyl 1-hydroxymethylcyclopropylsulfonylcarbamate (26.0 g, 103 mmol) in DCM (300 mL) was cooled to −78° C. To this solution was added diethylaminosulfur trifluoride (“DAST”, 41.0 mL, 310 mmol). The reaction mass was stirred at the same temperature for 30 min. The reaction mass was quenched with aqueous 1N NaOH solution. The organic layer was discarded and the aqueous layer was acidified to pH˜2 by using aq. 1.5 N HCl solution. The aqueous solution was extracted with DCM (50 mL×4). The combined organic layers were dried over anhydrous sodium sulfate; filtered; then concentrated to afford desired tert-butyl(1-(fluoromethyl)cyclopropyl)sulfonylcarbamate (19 g, 72%) as gummy solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.25 (sb, 1H), 4.75 (s, 1H), 4.63 (s, 1H), 1.44 (s, 9H), 1.28 (m, 2H), 1.07 (m, 2H). 19F NMR: −211.7 (1F).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:26]([CH3:28])[CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:26]([CH3:28])[CH3:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CC(C)c1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: CC(C)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-hydroxy-2-isopropylaniline (26 mg, 0.173 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.77 (t, J=1, 8 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 7.29 (brs, 1H), 7.27 (s, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.70 (s, 1H), 4.13 (sep, J=6.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCCl
Reactant: C1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCN1CCNCC1
Yield: 43.6 %

Procedure:
A mixture of 100 g (1.2 mole) of piperazine, 72 g (0.455 mole) of 3-chloro-N,N-dimethylpropanamine, hydrochloride and 110 g (1.3 mole) of sodium bicarbonate in 500 ml of ethanol was heated under reflux for 7 hr, allowed to cool, filtered and concentrated to dryness under vacuum. The concentrate was slurried in dichloromethane and filtered. The filterate was concentrated and then distilled under water pump pressure (~5 mm) to afford 34 g (44%) of the desired product, bp 100°-102°/5 mm.
Reaction SMILES: [ClH:1].N#N.C(OC([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH3:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)(C)(C)C>C(Cl)Cl>[ClH:1].[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[CH3:30])=[CH:27][CH:26]=1)#[N:29]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Yield: 100 %

Procedure:
Hydrogen chloride gas was introduced into a solution containing 3.7 g of N2 -tert-butoxycarbonyl-N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide dissolved in 100 mL of methylene chloride for 1 hour at room temperature. After completion of the reaction, the methylene chloride was removed under reduced pressure, thus obtaining a crude crystal. The crude crystal was washed with acetone to afford 3.1 g of the desired product (yield: 100%). Melting point: 59°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][OH:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][OH:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCO)cc1Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 2-chloro-4-(2-hydroxyethylthio)benzonitrile. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 451.0 (M)+.