Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][N:30]([CH3:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CN(C)c1nc2ccccc2[nH]1
Product: CN(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.25 g) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 59.5 mg of 153 following reverse phase HPLC purification. MS (Q1) 531.3 (M)+
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH-:11].[K+]>>[O:3]=[C:1]([CH3:2])[CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:10])=[O:11]
Reactant: [OH-]
Reactant: CC(=O)C1CCCCC1=O
Agent: [K+]
Product: CC(=O)CCCCCC(=O)O

Procedure:
7-Oxooctanoic acid was prepared by treatment of 2-acetyl cyclohexanone with aqueous potassium hydroxide (S. Hunig et al; Chem Ber 91, 129-133 (1958)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanine (2.72 g, 10 mmol), L-proline benzyl ester hydrochloric acid (2.42 g, 10 mmol), and HOBT (135 mg, 1 mmol) in tetrahydrofuran (60 ml) was added triethylamine (1.4 ml, 10 mmol) and DCC (2.43 g, 11.8 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (5.5 g) was subjected to silica gel column chromatography with Lobar® column C (Merck inc.) (toluene:acetone=9:1) to give 4.16 g of the compound (30).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[OH:7][N:8]=[C:9]([C:11]1[C:15]([NH:16]CCCOC)=[N:14][O:13][N:12]=1)N>>[NH2:16][C:15]1[C:11]([C:9](=[N:8][OH:7])[NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:12][O:13][N:14]=1
Reactant: COCCCNc1nonc1C(N)=NO
Reactant: COCCCN
Product: COCCCNC(=NO)c1nonc1N
Yield: 93 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step C, using 3-methoxy-1-propanamine as the starting material in 93% yield. LCMS for C7H14N5O3 (M+H)+: m/z=216.1. Step B: N′-Hydroxy-4-[(3-methoxypropyl)amino]-1,2,5-oxadiazole-3-carboximidamide
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl.O>[CH:16](=[N:9][NH:8][C:5]1[N:6]=[N:7][C:2]([Cl:1])=[C:3]([N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1cc(N2CC=CCC2)c(Cl)nn1
Agent: Cl
Solvent: O
Product: Clc1nnc(NN=Cc2ccccc2)cc1N1CC=CCC1
Temperature: 50 °C
Yield: 90 %

Procedure:
To a suspension of [6-chloro-5-(3,6-dihydro-2H-pyridin-1-yl)-pyridazin-3-yl]hydrazine (1.0 g) in 0.1 M HCl (40 ml) at room temperature was added benzaldehyde (1.05 eq.). The mixture was heated at 50° C. for 2 hours then allowed to cool, diluted with water (100 ml) and filtered. The resulting solid was dried in vacuo, and isolated as a yellow solid (1.25 g, 90%). 1H NMR (250 MHz, CDCl3) 11.65 (1H, br s), 8.31 (1H, s), 7.73 (2H, m), 7.38 (2H, m), 7.04 (1H, s), 5.97 (1H, m), 5.83 (1H, m), 3.80 (2H, m), 3.54 (2H, m), 2.40 (2H, m). MS (ES+) 314 [MH]+, 316 [MH]+.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCOc1ccccc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCOc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.25 g--see Preparation 8), 2-phenoxyethyl bromide (0.18 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.18 g.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].O1CCCC1.[C:15]([O-])(=[O:19])[CH:16]([CH3:18])[CH3:17].[Na+].Cl>O>[C:15]([NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 35.2 g (0.20 mol) of L-cysteine hydrochloride monohydrate in 100 ml of a mixture of 80% of tetrahydrofuran (THF) and 20% of water was stirred under nitrogen at room temperature and treated with 44.0 g (0.40 mol) of sodium isobutyrate. The reaction mixture (white slurry) was cooled to 0°-5° C. and, under nitrogen, 35 ml (0.21 mol) of isobutyryl anhydride was added dropwise. The resulting mobile suspension was stirred for 6h at room temperature, allowed to stand overnight, and finally heated under reflux for 4 h. The reaction mixture was cooled on an ice bath and 18 ml of concentrated hydrogen chloride was added. The organic phase was evaporated to give a colourless oil. The oil was washed with hexane and thereafter treated with ether to give 12.9 g of the title compound as a white solid, mp 103°-104° C. (recrystallized from butyl acetate), [α]D25 =+23.4° C. (c 5.0, H2O, pH=7.0), 1H-NMR (CDCl3): δ 1.2 (6H, d, CH3), 1.4 (1H, t, SH), 2.5 (1H, sept, CH), 3.1 (2H, m, CH2), 4.9 (1H, dt, NCH), 6.7 (1H, d, NH), 10.6 (1H, s, OH). 13C-NMR (CDCl3): δ 19, 19.5; 26.5; 36; 54, 172, 178. ms: 335 (M+ +2TMS, after silylation).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCO.O.[NH2:16][NH2:17]>>[C:5]1([CH2:4][C:3]([NH:16][NH2:17])=[O:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1ccccc1

Procedure:
Phenyl-acetic acid methyl ester (5 g, 33.3 mmol) was dissolved in hydrazine hydrate (25 mL) and EtOH (50 mL) and the reaction was heated in a sealed tube to 80° C. overnight. After cooling the reaction was concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CC[C@H](NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of tert-butyl trans-4-(benzylamino)cyclohexylcarbamate (730 mg, 3.6 mmol) (preparation 26) in dichloromethane (20 ml) was saturated with hydrogen chloride gas. The reaction mixture was stirred at room temperature for 2 hr and the solvent removed under reduced pressure to give a residue which was triturated with diethyl ether. The resulting solid was dissolved in water and solid sodium hydrogen carbonate added. The aqueous mixture was then extracted with ethyl acetate followed by dichloromethane. The organic extracts were combined, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (530 mg) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]([NH:30][C:31]([CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:32])([CH3:29])[CH3:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)NC(=O)Cc1ccc(CN)cc1
Product: CC(C)NC(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 63.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (162 mg, 0.38 mmol) and 4-(iso-propylcarbamoyl-methyl)-benzylamine (157 mg, 0.76 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1, 4:1, 2:1 and 1:1) to obtain 7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (117 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:19][CH2:18]1.C([Mg]Br)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:18][CH3:19])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a red solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (2.95 g, 13.0 mmol), Fe(acac)3 (512 mg, 1.45 mmol) and NMP (1.58 g, 16.0 mmol) in THF (400 mL), a solution of ethylmagnesium bromide (1.81 g, 13.6 mmol) in THF is slowly added at −77° C. The brown solution turns green-grey. The suspension is warmed to rt, stirred for 30 min before the yellow solution is again cooled to −70° C. and another portion of the Grignard reagent (1.38 g, 10.4 mmol) is added. The reaction mixture is warmed to rt, stirred for 16 h and then carefully quenched with 1 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-ethyl-6-methyl-isonicotinic acid tert.-butyl ester as a yellow oil which is dissolved in 4 N HCl in dioxane (50 mL). The solution is stirred at 50° C. for 16 h before the solvent is evaporated to give 2-ethyl-6-methylisonicotinic acid hydrochloride as a beige powder; LC-MS: tR=0.28 min, [M+1]+=166.25; 1H NMR (CDCl3): δ 8.19 (s, 2H), 3.12 (q; J=7.6 Hz, 2H), 2.84 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)=[CH:12][S:11][CH:4]2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl.CN(C)C(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:3]3[CH:4]([NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[C:2]3[OH:1])[S:11][CH:12]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: N#CC1=C(O)C2C(c3ccc(CO)cc3)=CSC2NC1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: N#CC1=C(O)C2C(c3ccc(C=O)cc3)=CSC2NC1=O

Procedure:
Tetrapropylammonium perruthenate (0.16 g, 0.46 mmol) was added to a solution of 4-Hydroxy-3-(4-hydroxymethyl-phenyl)-6-oxo-3a,6,7,7a-tetrahydro-thieno[2,3-b]pyridine-5-carbonitrile (0.55 g, 1.84 mmol) and 4-methylmorpholine N-oxide (0.65 g, 5.52 mmol) in 2:1 mixture of dichloromethane/N,N-dimethylacetamide (33 mL) at room temperature. The reaction was stirred till complete consumption of the starting alcohol, filtered over celite, filtrate washed with 1N HCl, dried (MgSO4) and concentrated to a brown solid. MS (ESI) m/e 294.9 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.01 (br s, 1H), 10.04 (s, 1H), 7.87 (d, J=9, 2H), 7.66 (d, J=9, 2H), 7.07 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[S:18][C@@H:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[S:18][C@@H:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H](O)[C@@H](Sc1c(OCc2ccccc2)cccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)[C@@H](Sc1c(N)cccc1OCc1ccccc1)c1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 3.5 h

Procedure:
To 3.91 g (8.34 mmol) of (+/−)-(2S,3S)-methyl 3-(2-(benzyloxy)-6-nitrophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoate in 45 mL of ethyl acetate was added 11.3 g (5.00 mmol) of tin(II) chloride dihydrate, and the solution was stirred at 22° C. for 3.5 hours. Water, NaHCO3, and ethyl acetate were added, and the mixture was stirred at 22° C. for 1.5 hours. The stirring was stopped, and the mixture left to stand for 16 hours. The organic layer was partially separated from the aqueous layer, and the remaining mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to give (+/−)-(2S,3S)-methyl 3-(2-amino-6-(benzyloxy)phenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoate, which was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added N-methyl piperazine (0.146 mL, 1.317 mmol) followed by diisopropyl ethylamine (0.229 mL, 1.317 mmol) and tetrabutyl ammonium iodide (162.15 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea (21 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.32 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.40 (m, 2H), 7.25 (s, 1H), 6.98 (m, 1H), 6.48 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 2.82-2.25 (m, 10H), 2.15 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:14]3[C:15]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][N:28]=[C:27]5[NH:23][N:24]=[CH:25][C:26]=45)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:21])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: NCc1ccnc2[nH]ncc12
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc21
Temperature: 120 °C

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide (60 mg, 0.201 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (36 mg, 0.243 mmol) and DIEA (70 μL, 0.401 mmol) were added. The mixture was heated at 120° C. overnight. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (14 mg, 0.094 mmol) and DIEA (35 μL, 0.200 mmol) were added and the mixture was heated at 120° C. overnight. The mixture was partitioned between water and EtOAc. The mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2) to give N-(4,4-dimethyl-1,2,3,4-tetrahydro-7-quinolinyl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a yellow solid. MS m/e 428.2(M+H)+. Calc'd for C24H25N7O—427.51.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[NH4+].[Cl-]>CC(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:18]2[CH2:17][CH2:16][CH:15]([O:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[C:11]([F:10])([F:25])[F:26])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)c1ccccc1OC1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 100-mL flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (3.80 g, 19.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (6.90 g, 24.5 mmol) and 2-propanol (25 mL). The suspension was treated with N,N-diisopropylethylamine (8.6 mL, 49 mmol) and stirred at room temperature for 10 min and then heated to 100° C. for 16 h. After this time, the mixture was cooled to room temperature, poured into a 250-mL separatory funnel containing saturated aqueous NH4Cl (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude solid was triturated in diethyl ether to yield the title compound as an off-white solid. MS (ESI, Q+) m/z 403, 405 (M+1 for 35Br and 37Br).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[O:15])=[CH:8][CH:9]=1)#[N:14]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: CC(CN)CNC(=O)c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNC(=O)c3ccc(C#N)cc3)ccc21
Yield: 50.1 %

Procedure:
A solution of the compound obtained in Step 2 (198 mg, 0.91 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (218 mg, 0.91 mmol), HATU (450 mg, 1.18 mmol) and TEA (0.381 mL, 2.73 mmol) in DMF (4.5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 100% ethyl acetate/hexane) to give the title compound (200 mg, 0.456 mmol, 50.0%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:15])([F:16])[F:14])=[C:8]([Br:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. E) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the contents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5 ml) was added, followed by the addition of sodium carbonate ((15 mg, 0.14 mmol). The remaining solution of bromine in acetic acid was added and the reaction mixture was left to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under vacuum to afford the title compound.