Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[CH3:36][C:37]1[O:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:41][C:40]4[O:43][C:37]([CH3:36])=[CH:38][CH:39]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: Cc1ccc(C=O)o1
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol), 5-methylfurfural (0.77 g, 0.007 mol), and acetic acid (1.15 g, 0.019 mol) in dichloroethane (100 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (4.1 g, 0.0195 mol) was added to the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×200 mL), and the combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel using 2%-5% methanol/dichloromethane as mobile phase to yield benzyl 4-[4-amino-3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (2.63 g, 0.0046 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.59 min. MS: MH+ 568.
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([CH3:47])=[C:7]([CH:21]([N:23]([C:27]3[CH:46]=[CH:45][C:30]([C:31](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:32])=[CH:29][CH:28]=3)[CH2:24][C:25]#[CH:26])[CH3:22])[CH:8]=2)[N:3]=1.[NH2:48][C@@H:49]([CH2:54][CH2:55][C:56]1[NH:60][N:59]=[N:58][N:57]=1)[C:50]([O:52]C)=[O:51].C(OC)(=O)CCC>>[CH3:1][C:2]1[NH:11][C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([CH3:47])=[C:7]([CH:21]([N:23]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([NH:48][CH:49]([CH2:54][CH2:55][C:56]4[NH:60][N:59]=[N:58][N:57]=4)[C:50]([OH:52])=[O:51])=[O:32])=[CH:45][CH:46]=3)[CH2:24][C:25]#[CH:26])[CH3:22])[CH:8]=2)[N:3]=1
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
Reactant: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)C(C)c1cc2c(=O)n(COC(=O)C(C)(C)C)c(C)nc2cc1C
Solvent: CCCC(=O)OC
Product: C#CCN(c1ccc(C(=O)NC(CCc2nnn[nH]2)C(=O)O)cc1)C(C)c1cc2c(=O)[nH]c(C)nc2cc1C

Procedure:
Using analogous procedures to those described in Example 1 pentafluorophenyl p-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzoate was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate and the resultant methyl butyrate was hydrolysed to give 2- {p-{N-[1-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzamido}-4-(tetrazol-5-yl)butyric acid in 25% yields m.p. 207° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C@H:24]([CH2:26][CH3:27])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@@H:22]([C@@H:24]([CH3:25])[CH2:26][CH3:27])[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:28]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of Example 28A (12.1 g) in methanol (20 mL) was added L-isoleucine tert-butyl ester hydrochloride (13.0 g, 58 mmol), sodium cyanoborohydride (7.3 g, 116 mmol), and acetic acid (2 mL). The resulting solution was stirred for 3 hrs at 25° C. and the methanol removed under vacuum, dichloromethane (500 mL) added, and the solution washed with aqueous NaHCO3 (2×300 mL). The organic layer was concentrated to give 12.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][S:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:28])=[O:27])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CCCCC1

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with cyclohexanesulfonyl chloride (0.053 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0195 g (50%) of the compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Methyl piperazine (0.072 mmol). The mixture can be microwaved at 120 degrees. The reaction mixture can then be filtered through a syringe filter and can be purified by prep-HPLC.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.88 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.45 ml of N-methylmorpholine in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -45° C. with stirring. To the cooled solution is added 0.52 ml of isobutylchloroformate. The reaction mixture is allowed to warm to -20° C. over a 10 minute period and is then cooled to -35° C. Following the addition of 1.9 g of L-phenylalanyl-1-aminoadamantane the reaction mixture is warmed to room temperature and allowed to stand overnight. The reaction mixture is filtered and the tetrahydrofuran is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with cold 1 M potassium bisulfate solution and saturated sodium chloride solution. Removal of the solvent and purification by chromatography on silica gel gives Boc-tyrosyl-D-methionyl-glycyl-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR39##
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:13]Br.Br>C(O)(=O)C.O>[Br:13][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: BrBr
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)CC(Br)C2=O

Procedure:
1-Oxoindane-5-carbonitrile is brominated with bromine in glacial acetic acid with addition of a catalytic amount of 48% strength HBr solution in water and affords 2-bromo-1-oxoindane-5-carbonitrile with a melting point of 115-118° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:41][C:42]2[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=2)=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:36]=1)#[N:30]>C1COCC1>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:41][C:42]2[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=2)=[C:35]([S:37]([N:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:7]2[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)(=[O:38])=[O:39])[CH:36]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCNC(Cn2cncn2)C1
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)cc(Cl)c2)C(Cn2cncn2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of tert-butyl 3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (29.5 mg, 0.11 mmol) and di-isopropyl-ethyl amine (28.5 mg, 0.22 mmol) in THF (2 ml) was added 5-cyano-2-(3,5-dichlorophenoxy)benzenesulfonyl chloride (40.0 mg, 0.11 mmol). The mixture was stirred at 50° C. overnight. The solvent was removed and the residue was diluted with CHCl3, washed with sat. NaHCO3 aq. and brine. The organic layer was dried over MgSO4. The solvent was evaporated in vacuo, and the resulting residue was purified by prep. TLC (MeOH/CHCl3= 1/10) to give tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-3-(1H-1,2,4-triazol-1-yl methyl)-1-piperazine-carboxylate (42.5 mg, 64.9%): HPLC-MS (ESI): Calcd for C25H26Cl2N6O5S [M+H]+ 593, found: 593.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:18])[CH:9]=2)=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Solvent: ClCCl
Product: ClCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
80 g (302 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol are suspended in 300 ml of dichloromethane, and 33 ml (453 mmol) of thionyl chloride are slowly added with cooling. The reaction mixture is stirred at room temperature for 3 h. The solvent is distilled off, co-evaporated 3 times with toluene and stirred with diethyl ether;
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O.O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(I)c1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (from Oakwood, 50.0 g, 271 mmol) in acetic acid (300 mL) was added N-iodosuccinimide (73.1 g, 325 mmol) and the resulting mixture was stirred on a heating mantle between 60˜80° C. over 3.5 hours then cooled to room temperature and stirred overnight. Water (500 mL) was added to the mixture in portions, which caused a dark solid to form. After stirring for 10 minutes, the solids were filtered, washing with additional water. The light to dark brown solids were dried under vacuum for 4 hours then air dried over the weekend to give 81.3 g (97%) of the desired product. LCMS calculated for C9H9ClI2 (M+H)+: m/z=310.9; Found: 311.0. 1H NMR (300 MHz, CDCl3): δ 13.21 (s, 1H), 7.71 (s, 1H), 2.65 (s, 3H), 2.63 (s, 3H) ppm.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.S(Cl)Cl>C(Cl)Cl.O>[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[N:17]([CH2:12][O:11][C:10]2[CH:9]=[CH:21][CH:20]=[C:19]([CH3:18])[C:6]=2[CH3:7])[CH2:16][CH2:15][N:14]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Agent: ClSCl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(OCC2=NCCN2COc2cccc(C)c2C)c1C
Reaction time: 2 h

Procedure:
11 g of triethylamine are added slowly dropwise at 0° C. to a solution of 20.4 g of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline in 200 ml of methylene chloride, followed by the slow dropwise addition of 5.15 g of freshly distilled sulfur chloride. The reaction mixture is then stirred for about 2 hours in an ice bath, the resultant solution is diluted with water and the organic phase is washed repeatedly with water, dried over sodium sulfate and concentrated completely. The residue is stirred in hexane and recrystallisation of the solid precipitate yields bis-(2,3-dimethylphenoxymethyl)-2-imidazoline)-1,1'-sulfide (compound 1) of the formula ##STR5## in the form of a light beige-coloured powder with a melting point of 112°-114° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.C(N(C(C)C)CC)(C)C.[C:14]1([C:20]2[CH:27]=[CH:26]C(CBr)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([C:20]2[CH:27]=[CH:26][C:3]([CH2:2][SH:1])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCS
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: SCc1ccc(-c2ccccc2)cc1
Reaction time: 0.04 h
Yield: 907.7 %

Procedure:
To a peptide synthesis vessel containing 2.3 grams (0.43 mmole) of NpSSMpact-PEG-PS resin 12 was added 15 mL of DMF, 0.25 mL (3.5 mmole) of β-mercaptoethanol and 0.4 mL (2.3 mmole) of diisopropylethylamine and mixture shaken for 2-3 minutes. The red colored mixture was then filtered and the process repeated two more times using the same quantities of BME and DIEA. The resin was then washed five times with DMF, three times with methanol, four times with CH2Cl2 and then three times with DMF. To the resin was then added 0.3 grams (1.21 mmole) of 4-phenyl benzyl bromide dissolved in 15 mL of DMF and 0.5 mL (2.87 mmole) of DIEA and shaken in the dark for 6.5 hours. After 6.5 hours, the mixture was then filtered and washed five times with DMF, three times with methanol and six times with CH2Cl2 in that order. The resin was then dried under pump vacuum to give 2.2 grams of 14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([SH:18])=[CH:10][C:9]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH:21]([Li])(CC)C.CN(C=O)C>C1COCC1>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[CH:10][C:11]([SH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[CH:19]=[CH:21]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Cc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(S)c(C(C)(C)C)cc21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester (prepared in Example EE; 20 g, 68 mmol) was dissolved in 100 mL of THF, cooled to −40° C., and treated dropwise with sec-butyllithium (1.3 M, 156 mL, 203 mmol). After the addition was complete, the reaction mixture was stirred at −30° C. to −45° C. for 30 minutes. To the mixture was added DMF (14.8 g, 203.39 mmol), and the solution was stirred at −35° C. for 30 minutes. The reaction mixture was slowly warmed to room temperature and was quenched with saturated NH4Cl solution. EtOAc (200 mL) was added; the organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was dissolved in 100 mL of THF and 2 mL of concentrated HCl and stirred at room temperature for 1 hour. The solution was diluted with EtOAc, washed with NaHCO3 solution and brine, and dried (MgSO4). The crude product was purified by flash silica gel chromatography to give the title compound. MS(APCI): 304 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[N:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCOCCn1nc(C(=O)OC)c2nc(Cl)nc(Cl)c21
Solvent: CS(C)=O
Product: CCOCCn1nc(C(=O)OC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The dichloro compound of Step 6 (1.98 g, 6.20 mmol) was dissolved in dimethyl sulphoxide (10 mL) and the solution treated with 2-amino-4-methylpyridine (1.34 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane (300 mL) and water (500 mL) and the dichloromethane layer separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 98:2. The crude product was triturated with ether (50 mL), filtered and concentrated in vacuo to yield the title product, 1.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:10]1([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][CH:16]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OCCN2CCOCC2)c1
Yield: 86 %

Procedure:
A mixture of 4-[2-(3-nitro-phenoxy)-ethyl]-morpholine (4.0 g, 13 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (100 mL) was hydrogenated under 50 psi hydrogen for 23 hours. The mixture was filtered through Celite, and the filtrate was evaporated in vacuo, providing 3.0 g, in 86% yield; 1H NMR (CDCl3) δ 2.58 (t, J=4.7 Hz, 4H), 2.78 (t, J=5.8 Hz, 2H), 3.65 (br, 2H), 3.73 (t, J=4.7 Hz, 4H), 4.07 (t, J=5.8 Hz, 2H), 6.24-6.34 (m, 3H), 7.05 (t, J=8.1 Hz, 1H).
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:48][C:49]1[CH:58]=[C:57]2[C:52]([CH2:53][N:54]([CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[C:55](=[O:59])[NH:56]2)=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:48][C:49]1[CH:58]=[C:57]2[C:52]([CH2:53][N:54]([CH:60]3[CH2:65][CH2:64][N:63]([C:1]([O:2][C@H:3]([CH2:18][C:19]4[CH:27]=[C:26]([CH3:28])[C:25]5[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=5)[CH:20]=4)[C:4](=[O:17])[N:5]4[CH2:10][CH2:9][CH:8]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH2:7][CH2:6]4)=[O:37])[CH2:62][CH2:61]3)[C:55](=[O:59])[NH:56]2)=[CH:51][CH:50]=1
Reactant: O=C1Nc2cc(F)ccc2CN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4ccc(F)cc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 7-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (56.2 mg, 1.0 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3:97:1 methanol/dichloromethane/triethylamine) to give 93 mg (53%) as a tan foam solid. Mass spec.: 776.48 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[C:24]4[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=4[F:25])[O:18][CH2:17][CH:16]2[NH:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:34]CCl>>[Cl:34][C:22]1[C:23]([F:25])=[C:24]2[C:19](=[C:20]([F:26])[CH:21]=1)[O:18][CH2:17][CH:16]1[C:11]2([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)ccc(F)c12
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)cc(Cl)c(F)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-1H-9-oxa-1-aza-phenanthrene (1.0190 g, 2.5475 mmol) was dissolved in 75 ml dichloromethane and cooled to 0° C. then triethylamine (1.1 mL) was added. The solution was stirred at 0° C. for 10 minutes then II was added slowly and the solution was stirred at 0° C. for 3 h. Then the reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with 50 ml of ice water. The organic layer washed with 50 ml of 1 N HCl solution and dried over sodium sulfate. The product was purified by column using EtOAc/Hex. as the eluent (gradient from 0/100 to 50/50 in 45 minutes). Yield: 124.0 mg, 11%. 1H NMR (CDCl3 400 MHz) δ 7.57 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.23 (dd, J=9.5, 6.6 Hz, 1H), 5.19 (dd, J=8.8, 6.6 Hz, 1H), 4.32 (d, J=11.7 Hz, 1H), 3.69 (s, 1H), 2.99 (d, J=13.1 Hz, 1H), 2.74 (td, J=13.1, 2.9 Hz, 1H), 2.64 (d, J=13.1 Hz, 1H), 2.20-2.11 (m, 1H), 1.62 (d, J=13.1 Hz, 2H), 1.19-1.06 (m, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][C:13]3[C:18]4[CH:19]=[C:20]([CH3:22])[O:21][C:17]=4[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=3)[CH2:9]2)C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=2)[CH2:9]1
Reactant: CCOC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2cc(C)oc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc(OC2CNC2)c2cc(C)oc2c1
Reaction time: 14 h

Procedure:
A mixture of ethyl 4-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-2-methyl-1-benzofuran-6-carboxylate (2.1 g, 4.77 mmol) in EtOAc/MeOH (10 mL/20 mL) and Pd/C (0.060 g, 10%, 0.048 mmol) was stirred for 14 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a bed of Celite washing with methanol. The sample was concentrated to give a pale white solid (quantitative yield), which was used without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35-1.52 (m, 3 H) 2.18 (s, 1 H) 2.47 (s, 3 H) 3.78-3.94 (m, 2 H) 4.00-4.13 (m, J=7.16 Hz, 2 H) 4.29-4.49 (m, 2 H) 5.11-5.27 (m, 1 H) 6.52 (s, 1 H) 7.05 (s, 1 H) 7.78 (s, 1 H); MS (ESI, pos): 276.