Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:21][C:22]1([CH3:46])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:24]=2[CH2:23]1>>[CH3:21][C:22]1([CH3:46])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40]([C:2]5[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][CH2:9][C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)=[N:6][CH:7]=5)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:24]=2[CH2:23]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1NCc1ccccc1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(NCc6ccccc6)c(NS(C)(=O)=O)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using N-{5-bromo-2-[(phenylmethyl)amino]pyridin-3-yl}methanesulfonamide (reagent preparation 39) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-D4): 8.26 (s, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.37 to 7.08 (m, 7H), 6.94 (d, 1H), 4.59 (s, 2H), 4.57 (s, 2H), 4.20 (m, 2H), 3.85 (m, 2H), 2.91 (s, 3H), 2.67 (t, 2H), 2.36 (s, 1.59 (t, 2H), 1.21 (s, 6H), 0.82 (s, 6H); MS (EI) for C32H36N6O3S: 585 (MH+).
Reaction SMILES: C(C1C=CC([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][CH:16]=3)[C:11](=[O:22])[N:10]2CCCNC(=O)OC(C)(C)C)=CC=1)#N.[N+](C1C=C2C(CCNC2=O)=CC=1)([O-])=O.[H][H]>[Pd].CO>[NH2:19][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:9][NH:10][C:11]2=[O:22])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc([N+](=O)[O-])ccc2CC1c1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1NCCc2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2

Procedure:
Compounds within the scope of the invention may be prepared as depicted in Scheme 1. In general, an aldehyde, such as 4-cyanobenzaldehyde, and an amine, such as N1-boc-1,3-diamino-n-propane can be reacted in a suitable solvent (eg., THF or chloroform) to form an imine intermediate. The solvent may then be evaporated under reduced pressure, and the residue redissolved in DMF. The imine is then reacted with 7-nitro-homopthallic anhydride, (i.e., 7-Nitro-1H-2-benzopyran-1,3(4H)-dione) to produce a 7-nitro-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(3-(4-cyanophenyl)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 1). The nitro group of the 7-nitro-3,4-dihydroisoquinolin-1(2H)-one can then be treated with a reducing agent, such as hydrogen in the presence of 10% palladium on carbon, in a suitable solvent (MeOH) to give a 7-amino-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(7-amino-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 13). The 7-amino-3,4-dihydroisoquinolin-1(2H)-one may be dissolved in a suitable solvent (eg., benzene) and then be treated with an organic isocyanates, such as 4-acetylphenyl isocyanates, in the presence of a strong base (eg, DIPEA) to produce a urea, such as tert-butyl {3-[7-({[(4-acetylphenyl)amino] carbonyl}amino)-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate (Intermediate 23), a compound which falls under the scope of the invention. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. For instance, a sulfide group may be oxidized to sulfoxide or sulfone groups by treatment with a suitable oxidizing agent (eg., m-chloroperbenzoic acid). Or, for example, the t-butylcarbamate group may be removed by treatment with a strong acid, such as trifluoroacetic acid, to give an amine product, such as 1-(4-acetylphenyl)-3-[2-(2-aminoethyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]urea (Compound 2). Details of certain specific chemical transformations are provided in the examples.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[CH2:5][CH2:4]1.CO[C@](C1C=CC=CC=1)(C(F)(F)F)C(O)=O.C=O>>[OH:1][CH2:2][CH:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[CH2:5][CH2:4]1
Reactant: O=C1CC[C@@H](CO)N1Cc1ccccc1
Agent: C=O
Agent: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Product: O=C1CCC(CO)N1Cc1ccccc1

Procedure:
The optical purity of the (S)-5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone was established by formation of the ester derived from (S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid ((-)-MTPA) following the procedure of Mosher, et al. (J. Org. Chem. 1969, 34, 2543). A single diastereomeric ester, as judged by 1H NMR and TLC, was obtained, and could readily be differentiated from the diastereomeric mixture (by the doubling of the CH2N and CH2O signals in the 1H NMR) produced when racemic 5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone was used to form the (-)-MTPA ester.
Reaction SMILES: CS(C)(=O)=O.Cl.[C:7](Cl)(=[NH:9])[NH2:8].C([O:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[NH:18][C:17]=1[NH2:26])=O)C.O.N>C(Cl)(Cl)Cl.O>[NH2:8][C:7]1[NH:9][C:14](=[O:13])[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:25])[NH:18][C:17]=2[N:26]=1
Reactant: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1 g methyl sulfone was heated to melting. 7 (106.22 mg, 1.37 mmol) was added and the resulting mixture was stirred and heated at 110-120° C. to dissolve completely. 5 (200 mg, 0.837 mmol) was added in one part to the reaction mixture. Stirring was continued for 30 minutes. About 10 mL water was added to quench the reaction. Ammonia water was added to neutralize the reaction mixture. Solid precipitated out. This solid was filtered. Obtained solid was dissolved in chloroform and methanol, dried (using Na2SO4) and recrystallized. The overall yield was 78%. TLC Rf 0.33 (chloroform-methanol 1:1); mp>250° C.; 1H NMR (DMSO-d6) δ 6.57 (bs, 2H, 2-NH2, exch); 7.04-7.17 (m, 3H, phenyl); 10.41 (s, 11-1, 9-NH, exch); 11.64 (s, 1H, 3-NH, exch). Anal. Calculated (C10H7ClN4O. 0.3CH3OH): C, 50.65; H, 3.38; N, 22.94; Cl, 14.52. Found: C, 50.91; H, 3.34; N, 22.60; Cl, 14.77.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(Cl)cc3)c3nc[nH]c3n2)CC1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2260 mg of the product obtained in stage 1 above are added. 80 mg of the expected product are thus obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([F:1])[N:7]=2)[CH2:15][CH2:14]1
Reactant: Fc1cc(C(F)(F)F)nc(F)n1
Reactant: NC1CC1
Product: Fc1nc(NC2CC2)cc(C(F)(F)F)n1

Procedure:
If, for example, 2,4-difluoro-6-trifluoromethylpyrimidine and cyclopropylamine are used as starting materials and the 4-cyclopropylamino-2-fluoro-6-trifluoromethylpyrimidine thereby formed is reacted with 3-methoxypropylamine, then the course of the reaction can be summarized by the following reaction scheme: ##STR7##
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].C=O.[C:8]([OH:11])(=[O:10])[CH3:9]>>[C:3]([N:2]([CH2:9][C:8]([OH:11])=[O:10])[CH3:1])(=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: CC(=O)O
Agent: C=O
Product: CC(=O)N(C)CC(=O)O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 1 L autoclave was charged with N-methylacetamide (IX) (160 g, 2.2 mole), Co(OAc)2.4H2O (33 g, 0.13 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately 0.5 h, rapid gas uptake was observed. The reaction mass was cooled to 85° C. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (180 mL, 2.97 mole) was delivered at 6 mL/min. The reaction was stirred at 85° C. for 30 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and assayed for N-acetylsarcosine. This resulted in a 92% yield of (XX).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][C:13]([NH:14][C:5]2[C:4]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH3:9])=[CH:11][CH:12]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: Oc1cccnc1O
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours; and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(p-tolylamino)-2,3-pyridindione in a red powder. The yield was 32%-54%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][O:10]C)[C:3]=1[Cl:12].Cl(O)(=O)(=O)=O>C1COCC1.O>[Cl:12][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1cccc(Cl)c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 99.4 %

Procedure:
To a solution of 15.0 g (0.074 mole) 1,2-dichloro-3-(2-methoxyethenyl)benzene in 150 ml of THF was added 15 ml of 35% perchloric acid in water. The reaction was refluxed for 3.5 hr then poured into ice/water. The aqueous layer was extracted two times with ether, the organics were washed with water, brine and dried (MgSO4). Evaporation of the solvent gave 13.91 g of crude 2,3-dichlorobenzeneacetaldehyde a yellow oil (99%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([CH3:16])[CH:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:16][C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[C:14]([CH3:15])=[CH:13][C:8]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(C)c(C2CO2)cc1C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4′-(2-bromoacetyl)-2′,5′-dimethylacetanilide (4.57 g) in ethanol (80 ml) was added sodium borohydride (608 mg) under ice-cooling, and the mixture was stirred for 1 hour. Acetic acid (3.7 ml) and water (200 ml) were added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (80 ml), and 5N aqueous sodium hydroxide solution (6.4 ml) was added to the solution under ice-cooling with stirring. The mixture was stirred for 30 minutes at room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. To the residue was added diethyl ether, and collection of the insoluble material by filtration gave 2′,5′-dimethyl-4′-oxiranylacetanilide (1.72 g).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl.Cl[CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>C(N(CC)CC)C>[CH3:1][N:2]([CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(CCN1CCOCC1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 51.7 %

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745), 29 mg 4-(2-chloroethyl)morpholine hydrochloride and 21 μL triethylamine were reacted in the same manner as in Example 746, to give 60 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methyl-(2-morpholin-4-yl-ethyl)amide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 45 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:11]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:24][NH:25][O:26][CH3:27].[Li]CCCC>>[C:1]([C:11]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:12]=1[C:13]([N:25]([CH3:24])[O:26][CH3:27])=[O:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CNOC
Reactant: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Yield: 94 %

Procedure:
Treatment of methyl 2-(1-decyn-1-yl)-4-(methyloxy)benzoate (191) (0.78 g, 2.58 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.80 g (94%) of the title compound (192) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.85-0.90 (m, 3H), 1.20-1.37 (m, 8H), 1.37-1.50 (m, 2H), 1.55-1.65 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 3.28 (br s, 3H), 3.61 (br s, 3H), 3.80 (s, 3H), 6.84 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 332 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23]#[N:24])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.CC([O-])(C)C.[K+].C1COCC1>C1COCC1>[CH:6]1[N:7]=[CH:8][N:9]2[CH:10]([C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14]([C:23]#[N:24])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][C:5]=12
Reactant: N#Cc1ccc(Cn2cncc2CCCCl)c(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCCc3cncn32)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[5-(3-chloropropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile (1.0 g, 3.0 mmol) in THF (16 mL) at 0° C. is added t-BuOK/THF (1.0 M, 6 mL, 6.0 mmol). The mixture is warmed up to ambient temperature and stirred for 2 h. The reaction mixture is quenched by saturated aqueous NH4Cl and partitioned between CH2Cl2 and brine. The organic layer is washed by brine, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 300 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.50-1.66 (m, 1H), 1.73-1.83 (m, 1H), 1.83-1.95 (m, 1H), 1.95-2.16 (m, 1H), 2.68-2.95 (m, 2H), 5.28 (dd, J=8.5, 5.2 Hz, 1H), 6.83 (s, 1H), 7.01-7.15 (m, 2H), 7.27-7.35 (m, 2H), 7.43-7.54 (m, 3H), 7.58 (s, 1H), 7.62 (d, J=8.3 Hz, 1H). Resolution of the enantiomers of the title compound is achieved by Chiral HPLC using the ChiralPak AD column with a 20% IPA/Hexane mobile phase.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[C:23]([Cl:31])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:20]([Cl:19])=[CH:26][C:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][C:23]=1[Cl:31])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: CS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.7 mL, 12.6 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (621 mg, 4.2 mmol) and 2,6-dichloro-4-(methylsulfonyl)aniline (1 g, 4.2 mmol) in DCM (15 mL) under nitrogen. Titanium tetrachloride (1 M, 2.5 mL, 2.5 mmol) was then added and the resulting mixture was stirred for 1 hour, warmed to room temperature, and stirred for an additional 4 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].[O-2:8].[Mg+2:9].[OH-]>O>[NH3:6].[OH2:2].[OH2:8].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mg+2:9]
Reactant: [O-2]
Reactant: [NH4+]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: N

Procedure:
reacting ammonium sulfate with magnesium oxide or hydroxide at a temperature of not more than 200° C. to form NH3, water and magnesium sulfate heptahydrate or an aqueous solution or slurry containing magnesium sulfate in a concentration of at least 15% by weight; recovering NH3 ;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:15])([CH2:13][OH:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[C:30]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=1[NH2:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C=O)C.O.C(OCC)(=O)C>[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[C:30]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=1[NH:32][C:10](=[O:12])[C@:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH2:13][OH:14]
Reactant: COc1ccc(N)c(C2OCCO2)c1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)[C@](C)(CO)NC(=O)OC(C)(C)C)c(C2OCCO2)c1
Temperature: 23 °C
Reaction time: 10 h
Yield: 43.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid (247.1 mg, 0.001127 mol) was dissolved in DMF, followed by N,N-diisopropylethylamine (0.892 mL, 0.00512 mol), and then 2-(1,3-dioxolan-2-yl)-4-methoxyaniline (200.0 mg, 0.001024 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (389.5 mg, 0.001024 mol) at 23° C. The reaction mixture was allowed to stir at 23° C. for 10 hours. Ethyl acetate (50 mL) was added, followed by water (10 mL). Organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2×10mL). Combined organic layers were washed with water (3×10 mL), brine and dried over Na2SO4. The crude product was purified via chromatography (SiO2, 12 g, 0-50% ethyl acetate/hexanes) to give the desired product (176 mg, 43%). 1H NMR (MeOD) δ: 7.98 (s, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.93 (dd, J=8.9, 2.9 Hz, 1H), 5.76 (s, 1H), 4.13-4.26 (m, 2H), 3.95-4.09 (m, 2H), 3.69-3.85 (m, 7H), 1.37-1.53 (m, 12H). MS (M+1): 397.20.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]>>[I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])[N:3]=1
Reactant: COC(=O)NCCCBr
Reactant: Cc1ccc2c(I)n[nH]c2n1
Product: COC(=O)NCCCn1nc(I)c2ccc(C)nc21

Procedure:
3-Iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine and methyl (3-bromopropyl)carbamate were treated in the similar manner to Reference Example 102(1) to give methyl [3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate [REx(104-3)] as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][C:20]=1Br)[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][C:20]=1[CH:26]=[CH:25][C:24]([O:28][CH3:29])=[O:27])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)c(CN(CC(F)(F)F)C(=O)OC(C)(C)C)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of 3-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)aminomethyl]-4-bromoanisole (48.19 g, 121 mmol), methyl acrylate (55 mL, 605 mmol), palladium acetate (1.36 g, 6.1 mmol), tri-o-tolylphosphine (3.69 g, 12 mol), and diisopropylethylamine (49 mL, 278 mmol) in acetonitrile (200 mL) was deoxygenated (3×evacuation/argon purge cycles), then was heated to reflux under argon in oil bath set at 80° C. After 6 hr additional palladium acetate (1.36 g, 6.1 mmol) and tri-o-tolylphosphine (3.69 g, 12 mmol) were added and the reaction was stirred under reflux for an additional 18 h. The reaction was concentrated to dryness, and the residue was taken up in 1:1 Et2O/petroleum ether (300 mL) and allowed to stand for 4 h. A gray-colored precipitate was filtered off and washed with a small volume of 1:1 Et2O/petroleum ether(˜100 mL). The orangish-red filtrate was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes). The resulting residue was taken up in hexane, and the mixture was allowed to stand for 2 hr, then was filtered to remove a yellow precipitate. Concentration of the filtrate left the title compound (45.85 g, 94%) as a yellow oil: TLC (20% EtOAc/hexane) Rf 0.50; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=16 Hz, 1H), 7.57 (d, J=9 Hz, 1H), 6.86 (dd, 1H), 6.74 and 6.72 (2s, 1H), 6.26 (d, J=16 Hz, 1H), 4.74 and 4.70 (2s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.80 and 3.66 (2m, 2H), 1.51 and 1.45 (2s, 9H).