Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:55]([CH3:57])[CH3:56])C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:24][CH2:25][CH:26]([C:29]([N:55]([CH3:57])[CH3:56])=[O:31])[CH2:27][CH2:28]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCC(C(=O)O)CC2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCC(C(=O)N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]piperidine-4-carboxylic acid (200 mg, 0.38 mmol) in DMF (4.0 mL) was added BOP (202 mg, 0.46 mmol), DIPEA (0.33 mL, 1.9 mmol), and finally N′N-dimethylamine (0.6 mL, 1.1 mmol). The reaction was allowed to stir at ambient temperature over a 16 hour period, after which it was judged complete by LCMS. The reaction mixture was diluted with EtOAc (50 mL), and washed with saturated NaHCO3(aq) (3×25 mL). The organic layer was dried over Na2SO4, decanted, and concentrated in vacuo. The resultant crude oil was purified on a normal phase SiO2 column (20%-80% EtOAc/Hexanes) affording the desired amide in >95% purity. HRMS: calcd for C26H32F4N4O3S+H+, 557.22040. found ([M+H]+), 557.22195.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[CH:16][C:15]=1[O:21][CH3:22]>CCO>[Br:13][C:14]1[CH:20]=[CH:19][C:17](/[N:12]=[C:5](/[O:4][CH2:2][CH3:3])\[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][C:15]=1[O:21][CH3:22]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: COc1cc(N)ccc1Br
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C/C(=N\c1ccc(Br)c(OC)c1)OCC
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A mixture of the product of Step 1 (54.2 g, 277 mmol) and 4-bromo-3-methoxyaniline (56.0 g, 277 mmol) in EtOH (500 mL) was stirred under nitrogen, at 22° C., for 20 hours. The mixture was filtered and concentrated, then stirred in ether (100 mL), filtered and concentrated. The residue was chromatographed on silica gel 60 (gradient elution, 0-50% EtOAc in hexane) to give the title product. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 1H); 6.43 (d, J=2.0 Hz, 1H); 6.30 (dd, J=8.4 & 2.4 Hz, 1H); 4.28 (q, J=7.1 Hz, 2H); 4.15 (q, J=7.1 Hz, 2H); 3.85 (s, 2H); 3.21 (s, 2H); 1.34 (t, J=7.2 Hz, 3H); 1.26 (t, J=7.0 Hz, 3H) ppm. LRMS (ESI) m/z 344.0 [(M+H)+; calcd for C14H19BrNO4: 344.0].
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1)[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[CH2:29][CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 2-ethyl-1H-benzo[d]imidazole were reacted to give 387. LCMS m/z: 518.3 (MH+)
Reaction SMILES: [CH3:1]ON(C)C(=O)C=C.[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+].C(OCC)(=O)C.[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:24][C:25](=[CH:26][C:27](=[O:23])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1]
Reactant: CCCC[Mg]Cl
Reactant: C1CCOC1
Reactant: C=CC(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCC(=O)C=C(C)C
Yield: 47 %

Procedure:
To a magnetically stirred and ice-cooled solution of N-methoxy-N-methyl-acrylamide (20 gram, 132.7 mmol) in anhydrous tetrahydrofuran (200 ml) in a nitrogen atmosphere was slowly added n-butylmagnesium chloride (132.7 ml, 2 M solution in diethyl ether, 265 mmol) and the resulting mixture was stirred for 30 minutes. The resulting mixture was allowed to attain room temperature and stirred for 40 hours. An aqueous ammonium chloride solution (15 gram dissolved in 100 ml water) was slowly added, followed by addition of ethyl acetate (100 ml). The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude 2-methyl-oct-2-en-4-one. Sepacore (80×150 mm column) separation (eluant: petroleum ether (40-60)/diethyl ether=95/5 (v/v)) gave 2-methyl-oct-2-en-4-one (Intermediate IIIb-1) as a colorless oil (9.30 gram, 47% yield). 1H-NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.2 Hz, 3H), 1.27-1.38 (M, 2H), 1.52-1.62 (m, 2H), 1.89 (s, 3H), 2.14 (s, 3H), 2.39 (t, J=7.4 Hz, 2H), 6.08 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=O)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[CH2:33]([NH:35][C:36]([NH:38][NH2:39])=[S:37])[CH3:34].O(Cl)Cl.[P+5]>O1CCOCC1>[CH2:33]([NH:35][C:36]1[S:37][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[N:39][N:38]=1)[CH3:34]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Reactant: CCNC(=S)NN
Agent: ClOCl
Agent: [P+5]
Solvent: C1COCCO1
Product: CCNc1nnc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a suspension of (S)-4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol) and N-ethylhydrazinecarbothioamide (21 mg, 0.18 mmol) in 1 ml 1,4-dioxane was added phosphorus (V) oxychloride (12.5 μL, 0.13 mmol). The mixture was stirred at 80° C. overnight. The solvent was evaporated and the residue was poured into water and ethyl acetate. The mixture was basified to pH 10 with sodium carbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was precipitated using diethyl ether, filtered, washed with cold diethyl ether and dried in a vacuum oven to obtain 14 mg (29% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][N:8]1[C@H:7]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:3][C:2]([C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[CH:7][CH:6]=[CH:5]5)=[CH:11][C:19]=3[CH2:20][CH2:6]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1ccc2ncccc2c1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ncccc5c4)cc3CC[C@@H]12
Yield: 46 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 6-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 107 mg (46%) of the title compound as an amorphous solid. mp 185°-190°. FDMS: m/e=356. α[D]589 =+78.73 (c=0.56, chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[I:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28]4)=[O:25])[CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(I)cn1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(C2CCNCC2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1CC1)c1ccc(C2CCN(c3ncc(I)cn3)CC2)cc1
Temperature: 25 °C

Procedure:
633 mg (2.5 mmol) 2-Chloro-5-iodopyrimidine, 757 mg (2.5 mmol) (S)-cyclopropanecarboxylic acid [1-(4-piperidin-4-yl-phenyl)ethyl]-amide (V.4) and 0.855 mL (5.0 mmol) DIPEA in 10 mL NMP are stirred for 2 h at 130° C. After cooling to rt the mixture is treated with water and the precipitate is collected by filtration and triturated with ether to yield the desired compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].BrBr.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1.[Cl:19]CCl>O.ClCC(Cl)(Cl)Cl>[ClH:19].[F:6][C:7]([F:17])([F:18])[O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:1]([NH2:2])[NH:16][C:11]=2[CH:10]=1
Reactant: [C-]#N
Reactant: ClCCl
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Agent: BrBr
Agent: ClCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cl
Product: Nc1nc2ccc(OC(F)(F)F)cc2[nH]1
Reaction time: 1 h

Procedure:
Sodium cyanide (1.79 9), dissolved in water (5.6 cc) is added dropwise to a mixture, cooled to 0° C., of bromine (5.8 9) and water (5.6 cc). After 1 hour's contact at 0° C., a solution of 4-trifluoromethoxy-1,2-benzenediamine (7 g) in tetrachloroethane (7 cc) is added dropwise. After 2 hours at 0° C., the reaction mixture is poured into water (500 cc). Dichloromethane (500 cc) is added and the mixture is stirred for 20 minutes. After settling has taken place, the aqueous phase is separated and washed with dichloromethane (2×150 cc) and alkalinized to pH 8 with sodium carbonate. The base is extracted with ethyl acetate (3×300 cc) and the organic phase is dried over magnesium sulphate and evaporated under reduced pressure. Crude base (9.5 g) is obtained, which is purified by preparative HPLC using a dichloromethane/ethanol mixture (95:5 by volume) as eluent. An oil is recovered, which is converted to a hydrochloride in ethyl ether. 5-Trifluoromethoxy-2-benzimidazolamine hydrochloride (4.8 g), m.p. 180° C., is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6]1.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37][N:17]2[CH2:18][CH2:19][CH:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: COCCn1cc(C2CCNCC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Yield: 87.9 %

Procedure:
Over a solution of 6.5 g (0.025 mol) of 1-(2-methoxyethyl)-3-piperidin-4-yl-1H-indole in 90 ml of dichloromethane and 3.9 ml (0.026 mol) of triethylamine, a solution of 7.2 g (0.026 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester in 15 ml of dichloromethane was added. The crude mixture was stirred at room temperature for 24 hours. After standard work-up and purification by chromatography over silica gel, 9.9 g (70% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester were obtained.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Cl.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:15]1[C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=[CH:2][CH:16]=1
Reactant: COc1ccccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COc1ccccc1OCCCc1cccc2onc(C3CCNCC3)c12
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6fluoro-3-[1-[3-(2-methoxyphenoxy)propyl[-4piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(O)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (36 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (4.66 mL, 26.7 mmol) and 2-hydroxy-2-methylpropanoic acid (2.78 g, 26.7 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-2-methylpropanoic acid (Fmoc-Pro-HOGly(Me)2-OH) (Compound SP636) (3.70 g, 8.74 mmol, 98%).
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[CH3:16])=[CH:5][N:6]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1C(=O)CCC1.CO>C(Cl)Cl>[CH2:17]([NH:24][C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[CH3:16])=[CH:5][N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Cc1n[nH]c2ccc(-c3cnc(I)o3)cc12
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1n[nH]c2ccc(-c3cnc(NCc4ccccc4)o3)cc12
Temperature: 165 °C
Yield: 30 %

Procedure:
The title compound was prepared from 5-(2-iodooxazol-5-yl)-3-methyl-1H-indazole, Scheme 5. A glass microwave reaction vessel was charged with 5-(2-iodooxazol-5-yl)-3-methyl-1H-indazole (0.050 g, 154 μmol), benzyl amine (0.120 mL, 1100 μmol) and NMP (1.0 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 165° C. for 10 minutes. The obtained product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to give the title compound (14 mg, 30% yield) LCMS (API-ES) m/z (%): 305 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (s, 1H) 7.48 (dd, J=8.72, 1.40 Hz, 1H) 7.42 (d, J=8.72 Hz, 1H) 7.38 (m, 2H) 7.31 (m, 2H) 7.22 (m, 1H) 7.14 (s 1H) 4.44 (s, 2H).
Reaction SMILES: [CH:1]1([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[C:7]([O:9][CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(OCC)C>C(#N)C.C(Cl)Cl>[Br-:23].[CH:1]1([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[C:7]([O:9][CH:10]2[CH2:14][CH2:13][N+:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH3:15])[CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Reactant: COC(=O)CBr
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)C[N+]1(C)CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Product: [Br-]
Reaction time: 2 h

Procedure:
To compound 4 (0.8235 g, 2.71 mmol) in 30 ml of dry acetonitrile, methyl bromoacetate (1.08 g, 7.06 mmol) was added at room temperature. The mixture was stirred for 2 h. Evaporation of acetonitrile gave a crude product. The crude product was dissolved in a small volume of methylene chloride and then poured into 100 ml of dry ethyl ether to precipitate. This procedure was repeated three times to obtain Compound (a) as pure product (0.9912 g, 80%). White powder, m.p.: 192-194° C. Analysis for C21H30BrNO5. Calcd: C, 55.27; H, 6.63; N, 3.07. Found: C, 55.11; H, 6.59; N, 3.03. 1H NMR (CDCl3, 500 MHz): 1.23-1.29, 1.31-1.37, 1.41-1.47, 1.53-1.67 [8H, m, (CH2)4], 2.18-2.23, 2.73-2.80, 4.04-4.16, 4.21-4.25 (6H, m, CH2NCH2CH2), 2.85 [1H, p, CHC(OH)], 3.57 (3H, s, NCH3), 3.80 (3H, s, CO2CH3), 4.66, 4.85 (2H, 2 dd, CH2CO2), 5.27 (1H, s, OH), 5.52 (1H, m, CO2CH), 7.25-7.28, 7.32-7.35, 7.57-7.59 (5H, m, Ph) ppm.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2=[CH:11][C:12]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[CH:19]=[C:9]2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[N:26]([CH3:41])[C:27]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][N:29]=1>>[ClH:20].[CH3:41][N:26]1[C:27]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][N:29]=[C:25]1[S:24][CH2:23][CH2:22][CH2:21][N:16]1[CH2:15][CH2:14][C:13]2[CH:19]=[C:9]3[O:8][CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:10]3=[CH:11][C:12]=2[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)N1CCOc2cc3c(cc21)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6c(cc5CC4)N(S(C)(=O)=O)CCO6)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 4-(methylsulfonyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine (30 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a yellow slightly hygroscopic solid (20 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49]OS(C)(=O)=O)[CH:39]=1>>[CH3:35][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:34])[C@H:9]([OH:25])[CH2:10][NH:11][C:12]3([C:15]4[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=4)[CH2:14][CH2:13]3)[CH:28]=2)[CH:39]=1
Reactant: COC(=O)c1cc(C)nc(OCCCCOS(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)CNC1(c2cc(C(C)(C)C)ccn2)CC1
Product: COC(=O)c1cc(C)nc(OCCCCOc2cccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC3(c4cc(C(C)(C)C)ccn4)CC3)c2)c1

Procedure:
The product is prepared according to the method described in example 43 (step a), starting from [(1S,2R)-3-[1-(4-tert-butyl-pyridin-2-yl)cyclopropylamino]-2-hydroxy-1-(3-hydroxy-benzyl)-propyl]-carbamic acid tert-butyl ester (building block C16) and 2-(4-methanesulfonyloxy-butoxy)-6-methyl-isonicotinic acid methyl ester (building block E1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:46]([C:69]([F:72])([F:71])[F:70])=[N:47][N:48]([C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([C:69]([F:70])([F:72])[F:71])=[N:47][N:48]([C:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-(trifluoromethyl)-1-trityl-1H-pyrazole and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(Cl)c(Cl)c2)c2cc(-c3ccccc3)ccc21
Yield: 30 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3,4-dichlorophenyl boronic acid. The title compound (46 mg) was obtained as a beige solid, (yield=30%).