Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:34][CH2:35]O>COCCOC.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>[CH:25]1([N:17]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]3[C:15]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)[CH2:27][CH2:35][CH2:34][CH2:26]1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CCO
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2nn(C3CCCC3)c3ncnc(N)c23)cc1OC
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of 3,4-dimethoxyphenylboronic acid (41 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.09 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA90 (8.4 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 340.2, found 340.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Yield: 80.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 4-acetoxycinnamic acid (2.0 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (2.6 g, 79%) as crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20]C)[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.B(Br)(Br)Br.CO.[C:38](=O)([OH:40])[O-:39].[Na+]>C(Cl)Cl>[CH:38]([OH:40])=[O:39].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (266 mg, 0.533 mmol) in anhydrous DCM (7.5 mL) under nitrogen atmosphere was treated dropwise with boron tribromide solution in DCM (1M, 0.533 mL, 0.533 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour (reaction not in solution—sticky orange gum had formed). A further portion of boron tribromide (1M, 0.533 mL) was added and the reaction mixture was stirred at room temperature for 1 hour (reaction still not in solution). Anhydrous methanol was added dropwise until the reaction was in solution. Reaction mixture was then stirred at room temperature for a further 30 min. Saturated aqueous sodium bicarbonate solution (10 mL) was added dropwise with care to quench the reaction, on addition of which both a white precipitate (suspended in the aqueous layer) and a dark green sticky gum (stuck to the side of the flask) formed. The aqueous and organic layers were applied to a hydrophobic frit and the organic layer collected and retained. The remaining green gum in the flask was dissolved in 1:1 methanol-dichloromethane, passed through a hydrophobic frit, combined with the retained organic and evaporated in-vacuo to yield a dark green sticky solid (265 mg). This was dissolved in DMSO (3×1 mL) and purified by MDAP Sunfire C18 column, eluting with solvents NB (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) (25 min run). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (86 mg, 33%). LCMS (System B) RT=1.63 min, ES+ve m/z 449/451 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][C:14]1[O:15][CH2:16][C:17]([CH:35]=[O:36])([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[N:18]=1.[CH:37]1[CH:42]=[CH:41][C:40]([O:43][C:44](Cl)=[S:45])=[CH:39][CH:38]=1>C1COCC1>[O:43]([C:44]([O:36][CH:35]([C:17]1([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[CH2:16][O:15][C:14]([CH3:13])=[N:18]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[S:45])[C:40]1[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=1
Reactant: CCCCCCCCc1ccc(CCC2(C=O)COC(C)=N2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC2(C(CP(=O)(OC)OC)OC(=S)Oc3ccccc3)COC(C)=N2)cc1
Reaction time: 0.83 h
Yield: 16.7 %

Procedure:
A solution of 0.46 mL of 2 M n-butyllithium in hexanes in 4 mL of THF at −78° C. was treated with 0.10 mL (0.92 mmol) dimethyl methylphosphonate and strirred cold for 50 min. (+/−)-2-Methyl-4-formyl-4-(2-(4-octylphenyl)ethyl)oxazoline (252 mg, 0.76 mmol, from EXAMPLE 2, Step B) was added and the resulting solution was stirred cold for 5 h. The mixture was treated with 0.32 mL (2.3 mmol) of phenyl chlorothionoformate and stirred cold for 1 h. The reaction was quenched with 2 mL of sat'd NH4Cl, then extracted with 30 mL of CH2Cl2. The organic layer was separated, washed with sat'd NaHCO3, dried and concentrated. Flash chromatography on silica gel using hexanes/EtOAc/CH3CN as the eluant afforded 75 mg (17%) of the title compound as a mixture of isomers: Mass spectrum (NH3—CI) 590 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN(C)CCCN
Product: COc1ccc(N(C)c2nc(NCCCN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and N′,N′-dimethyl-propane-1,3-diamine (16 μl, 0.070 mmol) by a procedure similar to Example 10 and was isolated as white powder (11 mg, 73%). 1H NMR (CDCl3): 7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8, 6.6 and 1.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49 (s, 3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[Cl:17])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 27.7 %

Procedure:
This compound was prepared according to the procedure used in Preparation 1. A mixture of 44.6 g (0.25 mol) of bis(2-chloroethyl)amine hydrochloride, 40.5 g (0.25 mol) of 3,4-dichloroaniline and 50.0 g (0.362 mol) of potassium carbonate in a total volume of 500 mL of n-butanol gave an oil as residue. Trituration of the oil with petroleum ether (30°-60°) gave 16.0 g (28%) of white solid, mp 62°-65° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]#[N:13])=[C:6]2[NH:5][CH2:4]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:31]>>[OH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]([NH2:13])=[O:31])=[C:6]2[NH:5][CH2:4]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2

Procedure:
The desired product was prepared form 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 364.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[N:13]1([CH2:18][C:19]2([CH2:22][NH2:23])[CH2:21][CH2:20]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:23][CH2:22][C:19]2([CH2:18][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:20][CH2:21]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: NCC1(CN2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc(F)c(C(=O)NCC2(CN3CCCC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 700 mg, 4.04 mmol), [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 655 mg, 4.25 mmol), HATU (1.69 g, 4.44 mmol) and DIPEA (2.1 mL, 12.12 mmol) were combined in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture divided into two portions and each loaded on to an SCX-2 column (20 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue taken up in DCM and purified on a silica column eluting with a 0-5% gradient of 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to yield the title compound as an orange gum which solidified on standing to an orange solid (472 mg, 38%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(=NO)C1C(=CC=CC=1)O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccn1
Reactant: CN(Cc1cc(Br)ccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(Cc1cc(Br)ccc1Oc1ccccn1)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 66.9 %

Procedure:
A mixture of (5-bromo-2-hydroxy-benzyl)-methyl-carbamic acid tert-butyl ester (581 mg, 1.22 mmol), 2-bromopyridine (238 μL, 2.44 mmol), Cs2CO3 (795 mg, 2.44 mmol), powdered 3 Å molecular sieves (366 mg), salicylaldoxime (33.5 mg, 0.244 mmol), Ca2O (9 mg, 0.06 mmol), and DMF (3 mL) was heated at 100° C. for 24 h. After cooling to rt, the mixture was diluted with DCM, filtered through diatomaceous earth, and concentrated. FCC purification (EtOAc/hexanes) gave the desired product (321 mg, 67%). 1H NMR (CDCl3, mixture of rotamers): 8.17-8.12 (m, 1H), 7.74-7.66 (m, 1H), 7.44-7.38 (m, 2H), 7.04-6.90 (m, 3H), 4.44-4.32 (m, 2H), 2.88-2.75 (m, 3H), 1.52-1.40 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=1.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:28]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=[C:2]([N:33]3[CH2:32][CH2:31][C:30]([NH:29][CH2:27][CH3:28])([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34]3)[N:7]2[N:8]=1
Reactant: CCNC1(C(N)=O)CCNCC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of 4-chloro-7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-1A-1e; 28 mg, 0.069 mmol) and triethylamine (14 μl, 0.10 mmol) in tetrahydrofuran (1 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1h; 13 mg, 0.076 mmol) and the mixture was stirred overnight. The mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-20-30% acetonitrile in methylene chloride as eluant afforded product I-1A-1i (20 mg, 54%): +APcI MS (M+1) 540.8; 1H NMR (400 MHz, CD2Cl2) δ 7.54 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 3H), 4.83-4.65 (br m, 2H), 4.20-4.05 (br m, 2H), 2.55 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 2.26-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10](=O)OCC2C=CC=CC=2)[CH2:4]1)#N.C[CH2:21][N:22](C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=C(S(C)=O)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=[C:10]([NH:9][C:5]4([C:21]#[N:22])[CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]4)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=3)(=[O:50])=[O:51])[C:33]2=[N:34][CH:35]=1
Reactant: N#C[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(C#N)CCCCC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 45 °C
Reaction time: 2.25 h

Procedure:
Benzyl N-[(1S,3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphere. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition of iPr2NEt (0.21 mL, 1.23 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at 45° C. then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH2:2]([O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][NH:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)[C@H]1C=CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C=CCN1
Reaction time: 3 h

Procedure:
(1:1) 1.5 g (0.006 mol) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester were dissolved at 5° C. in 10 ml trifluoroacetic acid and stirring was continued at room temperature for 3 hours. Evaporation of the solvent in vacuo gave 2.05 g (quant.) of (R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl ester trifluoroacetate (1:1) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 33.5 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.627 mmol), and hydrazine anhydrous (0.026 mL, 0.836 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered, and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (31 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.49 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.12 (m, 1H), 2.25 (s, 3H), 3.16 (m, 1H), 3.48 (m, 1H), 4.49 (m, 2H), 4.74-4.99 (m, 1H), 7.11 (t, J=8.3 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.74 (d, J=3.0 Hz, 1H), 7.89 (d, J=10.1 Hz, 1H), 9.97 (d, J=12.4 Hz, 1H), 12.03 (m, 2H).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:24])=[CH:26][CH:27]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 4-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1); the resulting solid was washed with diethyl ether to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[BrH:19].BrBr>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[Br:19]
Reactant: CSc1ccc(CC(=O)c2ccccc2F)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reaction time: 0.83 h

Procedure:
A 100 mL three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone from Step 2, (4.36 g, 16.7 mmol), acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL). The solution was stirred and treated with bromine (17 mL, 16.8 mmol, 1.0M in acetic acid) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca, 15 min. After an additional 50 minutes at room temperature, the solution was concentrated in vacuo to give a brown oil. The crude haloketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone as an oil that solidified upon standing (4.83 g, 85%): mp 58°-63° C. 1H NMR (CDCl3) 300 MHz 7.87 (td, J=7.6, 1.8Hz, 1H), 7.52 (m, 1H), 7.39 (d, J=8.3Hz, 2H), 7.27-7.03 (m, 4H), 6.34 (s, 1H), 2.45 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+ =338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])=[CH:8][C:9](=[O:22])[N:10]2[CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>C(O)C>[NH2:30][CH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([CH3:23])=[CH:8][C:9]2=[O:22])[CH2:16][CH2:17]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC(=O)CC3)c2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(N)CC3)c2c1
Reaction time: 1 h

Procedure:
To 1.5 mL of an ethanol solution containing 10 mg of 7-methoxy-4-methyl-1-(2-(4-oxocyclohexyl)ethyl)quinolin-2(1H)-one, 3.7 mg of ammonium acetate and 15 mg of molecular sieves 3A were added at room temperature, the mixture was stirred for 1 hour, then thereto was added 5.0 mg of sodium cyanoborohydride, and the mixture was stirred at the same temperature for 4 hours and 30 minutes. Thereto was further added 3.0 mg of sodium cyanoborohydride, and the mixture was stirred for 30 minute, and then left to stand overnight. The solvent was removed under reduced pressure, water and ethyl acetate were added thereto, the reaction mixture was adjusted to pH 3 to 4 (pH test paper) with 2.0 mol/L hydrochloric acid, and the aqueous layer was separated. The aqueous layer was added with ethyl acetate, and the resultant solution was adjusted to pH 8 to 9 (pH test paper) with a 2.0 mol/L aqueous sodium hydroxide solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 6.0 mg of a colorless oily substance, 1-(2-(4-aminocyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one.