Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:28])=[O:27])=[O:7])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN1C(=O)CCC1>[CH3:25][N:14]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:12]1[S:13][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)=[C:10]([C:26]([NH2:28])=[O:27])[N:11]=1
Reactant: CN1CCNCC1
Reactant: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(N(C)c4ccc5ncccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 54 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)amino]thiazole-4-carboxamide (100 mg, 0.24 mmol) and 1-methyl-piperazine (110 mg, 1.10 mmol) in NMP (3 mL) was heated at 150° C. for 1.5 hrs. The reaction mixture was diluted with ice-water (5 mL), and the resulting solids were collected by filtration and washed successively with water and ether to give 0.065 g (54% yield) of the titled compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH3:16])[C:4]1=[O:17])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH2:18]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH3:16])[C:4]1=[O:17])[CH3:19]
Reactant: CCC1(CC)C(=O)N(C)c2ccc(NC(C)=O)cc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(3,3-diethyl-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) in acetic acid (5 ml) at 0° C. is added nitric acid (fuming, 0.5 ml) drop-wise. The mixture is stirred at RT for 30 min and then poured into ice-water. The precipitate is collected by filtration and washed with water to give N-(3,3-diethyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1,38 g).
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1.C(Br)(Br)(Br)[Br:16].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCCl>[Br:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: N#Cc1cc(CO)c2ccccc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: N#Cc1cc(CBr)c2ccccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.4 %

Procedure:
To a solution of 4-(hydroxymethyl)-2-naphthalenecarbonitrile (200 mg) in dry DCE (5 mL), CBr4 (542.8 mg) and (Ph)3P were added, the resulting mixture was stirred at r.t. for 40 min and then quenched with 40 mL of water. The aqueous phase washed with DCM (3×40 mL). The combined organic extracts were dried, concentrated, and purified by flash chromatography (CH/AcOEt from 8:2 to 1:1) to give the title compound (216 mg) as a white foam.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH2:28])=[CH:18][CH:17]=1.C(O)C.[BH4-].[Na+]>O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: Nc1nccn1Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccn2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-Oxo-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.053 mol), 1-[(4-fluorophenyl)methyl]-1H-imidazol-2-amine and titanium(IV)isopropoxyde (0.055 mol) were stirred at 50° C. for 2 hours. Ethanol (350 ml) and sodium borohydride (0.53 mol) were added. The mixture was stirred at RT overnight and water was added. The mixture was filtered over decalite, washed with ethanol/CH2Cl2 and the solvent was evaporated. The residue was taken up in CH2Cl2, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1, 98/2, 97/3, 96/4 and 94/6). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 11.3 g (57%) of 1,1-dimethylethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-imidazol-2-yl]amino]-1-piperidinecarboxylate (intermediate 29).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[CH:12]([NH2:15])([CH3:14])[CH3:13]>CO.[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:15][CH:12]([CH3:14])[CH3:13]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)N
Agent: [Pd]
Solvent: CO
Product: CC(C)NCc1ccccc1N
Reaction time: 3 h

Procedure:
To a 500 ml 3-necked round bottom flask equipped with overhead mechanical stirrer, thermometer and nitrogen bubbler was charged 2-nitrobenzaldehyde (200 g, 1.32 mol) in methanol (1300 ml), to which was added isopropylamine (78.0 g, 113 ml, 1.32 mol) in one portion with stirring under nitrogen. The reaction mixture was then stirred for 100 minutes (followed reaction by GC), then added to a 4 litre stainless steel Parr hydrogenator, containing a suspension of 5% palladium on charcoal (13.24 g, 6% cat. loading) in methanol (500 ml) and the suspension hydrogenated under hydrogen at 60 psi for 3 hours. The suspension was filtered through a pad of celite, the pad washed with methanol (500 ml) and the combined filtrate evaporated under reduced pressure to leave a yellow oil, 2-amino-N-(1-methylethyl)-benzylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Si](C)(C)C)[CH:25]=[CH2:26].B(F)(F)F.CCOCC>ClCCl.CCOCC>[CH2:26]([C@H:15]1[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9](=[O:23])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1
Yield: 98 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added allyltrimethylsilane (0.228 parts, 2 mmol). Then Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise to reaction mixture at 30° C. was stirred for 30 mints. and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 7-allyl-6-benzyl-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (7f) (viscous liquid, 0.343 parts, 0.98 mmol) in 98% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]#[C:14][C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1.CO>O1CCCC1.[Pd]>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[CH2:13][CH2:14][C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1
Reactant: COc1cc(OC)c(F)c(C#Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(F)c(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-[(2,6-difluoro-3,5-dimethoxyphenyl)ethynyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (490 mg, 1.08 mmol) in tetrahydrofuran (8 mL)/methanol (10 mL), Pd/C (10% w/w, 365 mg, 0.343 mmol) was added. The resulting mixture was stirred under H2 at ambient temperature. After 24 hr, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (400 mg, 81%). LCMS calculated for C22H19F2N3O4S (M+H)+: m/z=460.1. Found: 460.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](n2ccnn2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](n2ccnn2)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Methyl sulfonyl chloride (2.84 g, 24.8 mmole) was added slowly to an ice cooled solution of trans 3-hydroxy-4-(1,2,3-triazol-1-yl)-1-N-(tert.-butoxy carbonyl) pyrrolidine (3.16 g, 12.4 mmol) and triethylamine (4.36 ml, 31.3 mmol) in dry CH2Cl2 (10 ml). The reaction mixture was stirred under N2 at room temperature for 22 hrs and washed with saturated NaHCO3 and brine solution. The dichloromethane layer was dried over Na2SO4 and concentrated to give the title product. Yield 4.0 g (97%). 1H NMR (CDCl3) δ: 1.5 (S, 9H), 3.07 (s, 3H), 4.07 (m, 4H), 5.43 (m, 2H), 7.70 (S, 1H), 7.90 (S, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO.C(OCC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Yield: 44.6 %

Procedure:
0.2 g (0.769 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate is added at a temperature in the region of 20° C. to a suspension of 0.02 g (0.188 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.079 g of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate, in the form of a brown solid; EI: m/z=230 (M+) base peak, m/z=202 (M-C2H4+), m/z=157 (M-C2H5O+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:20]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:20])=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1C
Reactant: C1COCCO1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-formyl-3-methyl-thiophene-2-carboxylic acid methyl ester (3.2 g, 17.4 mmol) in dioxane (20 ml) was added 2-methyl-2-butene (15 ml) and a solution of Na2ClO2 (4.71 g, 52.1 mmol) and NaH2PO4 (4.71 g, 39.2 mmol) in water (15 ml). The mixture was stirred at rt for 1 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc and dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (3.13 g, 90% yield)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[Cl:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccc1Cl
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3Cl)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chlorobenzyl chloride (0.38 mL) as starting materials, 5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=2)(=[O:25])=[O:24])=[N:10][CH:11]=1
Reactant: Nc1ccc(COCC(F)(F)F)cn1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1ccc(COCC(F)(F)F)cn1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 5-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.06 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.078 g) as an off-white solid (0.056 g). MS (ESI−): 413.1 ([M−H]−).
Reaction SMILES: [OH-:1].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>C1(C)C=CC=CC=1>[C:4]([C:15]1[CH:16]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[S:12][CH:13]=[CH:14][C:10]=1[CH2:9][CH2:8]2)(=[O:1])[CH3:3]
Reactant: Oc1c(-c2cccc(F)c2)sc2[n+]1CCc1ccsc1-2
Reactant: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2

Procedure:
A solution of 0.303 g of 5,6-dihydro-3-hydroxy-2-(m-fluorophenyl )-thiazolo[3,2-a ]thieno[2,3-c ]pyridinium hydroxide (internal salt) and 0.145 ml of 3-butyl-2-one in 5 ml of toluene was heated under reflux for 1 hour. The solvent is evaporated in vacuo and the residue is chromatographed over silica gel with toluene/ethyl acetate (1:1). After recrystallization from ethanol, there was obtained 10-acetyl-4,5-dihydro-8-(m-fluorophenyl)7H-thieno[2,3-a]quinolizin-7-one of m.p. 109°110°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([OH:20])[CH3:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([O:20][C:1](=[O:3])[CH3:2])[CH3:19])=[O:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Acetyl chloride (0.39 mL, 5.5 mmol) and (1R,2R)-2-hydroxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (32) (2.0 g, 3.6 mmol) were dissolved in 25 mL of anhydrous dichloromethane. A solution of pyridine (0.5 mL, 5.5 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration and drying under vacuum, the crude product (33) (2.0 g, 95% yield) was isolated and used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.11 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.05 (s, 3H), 2.95 (dd, J=13.6, 6.4 Hz, 1H), 3.00 (dd, J=13.6, 6.4 Hz, 1H), 4.50 (dd, J=13.6, 6.4 Hz, 1H), 4.93 (m, 2H), 4.98 (d, 1H, NH), 5.12 (s, 4H), 6.66 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.29-7.45 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:25]=1)[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38]([N:7]([CH2:6][C:5]1[CH:23]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:25]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:12][CH2:13]1)=[O:39]
Reactant: COc1cc(CNC2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(-c2ccncc2)c1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1cc(CN(C(=O)c2sc3c(F)ccc(F)c3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(-c2ccncc2)c1

Procedure:
Biaryl amine 243 (18 mg, 42 μmol) is treated with acid chloride 8 (14 mg, 51 μmol) using Method D to afford the title compound.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42]C)=O)[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71]C=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.C1(N)CC1>>[CH:67]1([CH2:54][NH:52][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:5])[CH3:4])[CH:31]=3)[CH:36]=2)=[O:42])[CH2:72][CH2:71]1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: NC1CC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NCC3CC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.78 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopropylamine hydrochloride (405 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.59 g) as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(NC(=O)c2ccc(NS(=O)(=O)N(C)C)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 30 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (500 mg, 1.20 mmol) was reacted with dimethylaminosulfonyl chloride to yield 190 mg (30%) of title compound as an orange solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][C@H:12]1[NH:17][CH2:16][C@@H:15]([CH2:18][OH:19])[O:14][CH2:13]1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1>CC#N>[NH2:20][C:21]1[N:26]=[C:25]([N:17]2[C@H:12]([CH3:11])[CH2:13][O:14][C@H:15]([CH2:18][OH:19])[CH2:16]2)[CH:24]=[C:23]([Cl:28])[N:22]=1
Reactant: C[C@@H]1CO[C@H](CO)CN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In a 2-5 mL microwave vessel Hunig's base (0.59 mL, 3.35 mmol) was added to [(2S,5R)-5-methyl-2-morpholinyl]methanol hydrochloride (208 mg, 1.12 mmol) in CH3CN (3 mL), and then 2-amino-4,6-dichloropyrimidine (174 mg, 1.06 mmol) was added. The mixture was heated with stirring in a microwave reactor at 160° C. for 1 hour. HPLC indicated complete conversion. The mixture was filtered through a 0.45 um filter disc, evaporated, and the product was purified further by chomatography (Analogix SF25-40 g silica column) eluting with 2-5% CH3OH—CHCl3 to afford the title compound (258 mg) as a white foam. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH3:26][N:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)=[O:33])[CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (0.04 g, 0.111 mmol, example 60), 1-methyl-1H-pyrazole-4-carboxylic acid (0.021 g, 0.167 mmol) and Hunig's base (0.036 g, 0.278 mmol) in EtOAc (2 mL) was added propylphosphonic acid anhydride (cyclic trimer) solution (50% in EtOAc, 0.177 mL, 0.25 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was diluted with EtOAc, poured into a sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.036 g, 75.1%) as a colorless amorphous solid. MS: 432.4 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH3:30])[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.