Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:7]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:10]2[S:3][CH:4]=[CH:5][C:6]1=2
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2sccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Sodium hydride (32 mg, 60%), was added to a solution of ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (0.13 g) (from Preparation 4) and the reaction stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (0.22 g) was added and stirring continued for a further 2 hours. The reaction was quenched by addition of water and extracted with ether. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatogaphy using isohexane-5% ethyl acetate as eluent to give the product as a yellow solid (0.15 g, 64%), NMR d(DMSO) 1.24 (3H, t), 4.22 (2H, q), 5.73 (2H, s), 6.63 (1H, d), 6.98 (1H, dd), 7.25 (2H, m), 7.37 (1H, s), 7.55 (1H, d); M/z (+) 354 (M+), 214, 158, 129.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:27]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]4[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:4][CH:3]=3)[CH2:32][CH2:31]2)[CH2:27]1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CNC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 3-piperazin-1-yl-azetidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2cccs2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)s2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc-hexanes) gave the product as a yellow foam (0.031 g, 11% yield). MS: m/z 529.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=3[CH:15]=2)[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3,5-difluorobenzene boronic acid generally according to the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.04 (s, 1H), 7.61-7.57 (m, 2H), 7.52-7.45 (m, 2H), 7.23-7.17 (m, 2H), 4.72 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 304 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.[Br:18]Br>C(O)(=O)C.C(Cl)Cl>[Br:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[N:7]([CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1)[CH2:16]2
Reactant: BrBr
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.87 mmol) was dissolved in acetic acid (2 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (0.5 mL) dropwise over 5 min. After stirring for at room temperature for 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 0.16 g (59%) which was used immediately without further purification. LC/MS: tR=0.91 min, 310.15 (MH)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=3)C(OC(C)(C)C)=O)[N:12]3[N:31]=[CH:32][CH:33]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([NH:16][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)[CH:25]=3)[N:12]3[N:31]=[CH:32][CH:33]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1c(N[C@H]2CC[C@H](N)CC2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1cccc(I)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@H]2CC[C@H](N)CC2)nc2ccnn2c1Nc1cccc(-c2cccnc2)c1

Procedure:
The title compound and Boc protected intermediate were synthesised in the same manner as above using N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(3-iodophenyl)carboxamide, pyridine-3-boronic acid, Na2CO3 palladium (II) acetate and triphenylphosphine. The title compound (6.1 mg, 15% yield as 3 trifluoroacetic acids salt) was obtained. The HPLC retention time and ESI/MS data for this compound are shown below.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[N:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[NH:29][CH:30]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:31]([C:28]3[NH:29][CH:30]=[N:26][N:27]=3)(=[O:33])=[O:32])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)c1nnc[nH]1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2nnc[nH]2)no1

Procedure:
Method as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (292 mg, 0.83 mmol) and 4H-1,2,4-triazole-3-sulfonyl chloride (preparation 24) (208 mg, 1.24 mmol) as starting materials.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1>O1CCCC1>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)cc1
Yield: 88 %

Procedure:
Ethylmagnesium bromide (5.4 mL, 3 M solution in tetrahydrofuran) was added dropwise to the solution of 4-bromobenzaldehyde (2.0 g, 10.8 mmol) in tetrahydrofuran (30 mL) at −30° C. Then the resultant mixture stirred at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride aqueous. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 1-(4-bromophenyl)propan-1-ol (2.0 g, 88%). 1H NMR (300 MHz, d6-DMSO): δ 7.49 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.20 (d, J=4.5 Hz, 1H), 4.45-4.41 (m, 1H), 1.63-1.53 (m, 2H), 0.80 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[K+].CS(C)=O>O>[C:13]([C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:2][C:3]#[N:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 50.9 g (0.168 mole) of α,4-dichloro-2-(benzoyl)-benzenepropanenitrile, 17 g (0.14 mole) of potassium carbonate, 50.9 g (0.5 mole) of potassium bicarbonate and 510 ml of dimethyl sulfoxide was stirred at room temperature for 48 hr. The mixture was diluted with 1.5 l of water, and the resulting percipitate was collected by filtration. Recrystallization from a mixture of methylene chloride and ether gave off-white prisms, mp 89°-91°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (63 mg, 30%)
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].Cl.CN(C=O)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
BOC-Thr(Bzl)-OH (32.88 g, 0.15 M) was dissolved in THF (100 ml). HOBT (20.94 g, 0.155 M) and H-Pro-OBzl.HCl (37.47 g, 0.155 M) were added thereto, and DMF (200 ml) was added to prepare a solution. WSCI (28.37 ml, 0.155 M) was added dropwise during 10 minutes while cooling with a freezing mixture, then the mixture was stirred at room temperature overnight. The solvent was distilled off in vacuo. Ethyl acetate (500 ml) was added to the residue, which was then washed with 5% aqueous sodium bicarbonate (twice), saturated sodium chloride solution, 1 N HCl (twice), saturated sodium chloride (twice) and water, in that order. After drying with anhydrous sodium sulfate, the solvent was distilled off and the mixture was concentrated in vacuo to obtain oil substance [5] (57.41 g, yield: 77.1%).
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O.[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24]>CC(O)=O>[CH3:19][O:20][C:21](=[O:26])[C:22]1[CH:4]=[CH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:25][C:23]=1[CH3:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: CN(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
4.59 g (16.3 mmol) of the above prepared 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 1.86 g (1.0 eq.) of 3-aminocrotonic acid methyl ester was dissolved in 50 ml of AcOH and heated to reflux for 4 h. After cooling, the bulk of the solvent was evaporated i. V., the residue dissolved in AcOEt, and washed with water and brine. Drying over sodium sulfate, evaporation of the solvents and flash chromatography (SiO2, hexane/AcOEt=8/2) delivered finally 2.40 g of the title compound as light yellow waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH2:28])=[N:9]1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH:28][C:35]([C@H:32]2[CH2:31][C:30](=[O:29])[NH:34][CH2:33]2)=[O:36])=[N:9]1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2F)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2F)c1)C(F)(F)F
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared in Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (32 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]>C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 4 h
Yield: 83.6 %

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.5 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 49, and the solution is allowed to stand at room temperature for 4 hours. To the solution is added 200 ml of petroleum ether and the resulting mixture is shaken thoroughly. After the supernatant is removed by decantation, the residue is diluted with 50 ml of water and extracted three times with 100 ml each of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether is added to the viscous residue to give 0.37 g of 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as colorless crystals melting at 135°-139° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4](Cl)[N:3]=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1nccc(NCC2(CO)CCC2)n1

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (1.46 g, 6.0 mmol) were added ethanol (40 ml), cyclohexene (15 ml) and palladium hydroxide (0.2 g) in a nitrogen stream, and the mixture was refluxed for 2 hours. The reaction mixture was filtered and the solvent in the filtrate was distilled away under reduced pressure to give white amorphous crystals (1.34 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH2:33])[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:42](O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][CH3:42])[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (20.4 mg, 0.037 mmol), 37% HCHO solution (3.0 mg, 0.037 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH3CN (7.0 mg) in methanol (0.2 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (8 mL) and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:53]=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(CO)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(CO)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminobenzyl alcohol as the aniline component. (15%, MS=613.3 (M+H))
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[C:15]([NH:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Yield: 21.5 %

Procedure:
To a stirred solution of compound ethyl 2-amino-2-cyanoacetate (0.64 g, 5 mmol) in DCM (15 mL) was added a saturate solution of NaHCO3 in water (15 mL). With vigorously stirring, benzoyl chloride (0.84 g, 6 mmol) was added. The reaction mixture was stirred at ambient temperature for additional 30 min at which time it was extracted with DCM (3×15 mL). Combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered, concentrated in vacuo. Resulted residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-benzamido-2-cyanoacetate (0.25 g, 22%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 7.83-7.85 (m, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 2H), 7.02 (d, J=7.0 Hz, 1H), 5.72 (d, J=7.5 Hz, 1H), 4.40 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 233 [M+H+].
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8]>O.C(O)(=O)C>[N:1](=[C:11]([C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[OH:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
A solution of sodium nitrate (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, (100 ml.) was added and the mixture extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([SH:22])=[N:10][C:9]=2[N:23]=1.[ClH:24]>O.CC#N>[Cl:24][C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([S:22][S:22][C:11]3[N:12]=[C:13]([NH:14][C@@H:15]([CH2:16][OH:17])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:8]4[S:7][C:6]([Cl:24])=[N:23][C:9]=4[N:10]=3)=[N:10][C:9]=2[N:23]=1
Reactant: Cl
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CC(C)C)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Temperature: 2.5 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Sodium nitrite (5.19 g, 75 mmol) in water (25 mL) was added dropwise at 0° C. to (2R)-2-[[2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentan-1-ol (7.50 g, 25 mmol) in conc. HCl (150 mL) and CH3CN (150 mL). The reaction mixture was stirred for 18 h at 0-5° C., and then poured onto ice (500 mL), and extracted with EtOAc. Any remaining solid was filtered off. The combined organic phases were washed sequentially with saturated NaCl solution and saturated aqueous NaHCO3 solution. The organic phase was dried and evaporated and the solid previously filtered off was added to this. The total solid was slurried in EtOAc, which after filtration provided the title compound (6.3 g, 80% yield) as a solid.