Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=[C:10]([O:12][CH3:13])[N:11]=1.CO.[OH-].[Na+].Cl>O>[CH3:13][O:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(OC)nc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(OC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A suspension of 40 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester, 2.0 mL of methanol and 0.5 mL of 2 M sodium hydroxide were stirred at ambient temperature for 18 hours. The reaction was diluted with 10 mL of water and then adjusted to pH 4 with 1 M HCl providing a precipitate. The precipitate was collected by filtration and washed with 5 mL of water and dried in vacuo (40° C., 10 torr) to provide 22 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (500 MHz, dmso-d6) δ0.98 (t, J=7.5 Hz, 3H), 2.89 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 4.87 (s, 2H), 5.48 (s, 2H), 7.17 (d, J=7.3 Hz, 2H), 7.31 (m, 3H), 7.50 (s, 1H), 7.93 (s, 1H), 12.89 (bs, 1H)
Reaction SMILES: [C:1](C1C=CC(C#N)=CN=1)(C)(C)C.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[N:18]=1)([CH3:16])([CH3:15])[CH3:14].C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1.[BH4-].[Na+]>>[C:13]([C:17]1[N:18]=[C:19]([CH3:25])[C:20]([CH:21]([NH2:22])[CH3:1])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C#N)cn1
Reactant: Cc1nc(C(C)(C)C)ccc1C#N
Agent: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(C(C)(C)C)ccc1C(C)N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 6-tert-butylnicotinonitrile starting from 6-tert-butyl-2-methylnicotinonitrile (intermediate 31) (100 mg, 0.57 mmol), used crude from the above described description; MeMgBr 1.4 M 75/25 toluene/THF (1.4 ml, 1.4 mmol) and NaBH4 (55 mg, 1.4 mmol). Purified by normal phase chromatography with 20% MeOH/CH2Cl2. (Yield 31.5 mg, 29%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9 H), 1.36 (d, J=6.64 Hz, 3 H), 2.56 (s, 3H), 4.32-4.40 (m, 1 H), 7.15-7.19 (m, J=8.20 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[N:5].[C:6]([N:14]=[C:15]=[O:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[NH:5]=[C:4]1[CH2:3][N:2]([CH3:1])[C:15](=[O:16])[N:14]1[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CNCC#N
Solvent: C1CCOC1
Product: CN1CC(=N)N(C(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of N-methylaminoacetonitrile (6.19 g) in anhydrous THF (100 mL) was added benzoyl isocyanate (13.0 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.6 g).
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17]C)=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O[Li].O>>[OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Li]O
Solvent: O
Product: O=C(O)C1(O)CCCc2ccc([N+](=O)[O-])cc21

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 1-hydroxy-7-nitrotetralin-1-yl-carboxylic acid, methyl ester (2.0 g; 8.3 mmol; from step (i) above) and LiOH.H2O (0.7 g; 16.6 mmol). Yield 1.72 g (88%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:5]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:32]>O1CCCC1>[C:34]1([CH3:39])[C:33]([C:31]([CH2:30][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:5]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2=[O:3])=[O:32])=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
60% Sodium hydride (1.6 g) was suspended in tetrahydrofuran (100 ml), 2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (7.23 g) was added thereto under ice-cooling, and the resultant mixture was stirred for one hour. Subsequently, 2-bromo-2′-methylacetophenone (4.88 g) was added thereto, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. Ice-water was added to the residue. The resultant mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 7.8 g of the title compound (yield: 79%)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[N:28]=[CH:27][N:26](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:25]=5)[CH:22]=4)[N:17](C4CCCCO4)[N:16]=3)[CH:10]=2)=[O:7])=[CH:2]1>Cl.O1CCOCC1>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccoc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
3-Furyl-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and was purified by preparative HPLC. (0.034 g, 37% yield over 2 steps): 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.28 (d, 2H), 7.88 (d, 1H), 7.81 (d, 1H), 7.70 (d, 1H), 7.65 (t, 1H), 7.55 (t, 1H), 7.01 (d, 1H); ES-MS (m/z) 371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]1=[O:24]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:10]1=[O:24]
Reactant: COc1ccccc1N1CC=CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
A solution of (S,Z)-tert-butyl 1-(2-methoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (30 mg, 0.090 mmol) in EtOAc (2 mL) was purged with argon for 5 min. Then, 5% Pd/C (25 mg, 0.24 mmol) was added. The reaction mixture was stirred under a hydrogen balloon for 2 hr. The reaction mixture was filtered and the filtrate was concentrated to afford (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamate (28 mg, 0.084 mmol, 93% yield) as a foam. Anal. Calcd. for C18H26N2O4 m/z 334.4. found: 335.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[C:7]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([Br:23])=[CH:18][C:17]=1F)=[C:8]([NH:11][CH:12]1[CH2:14][CH2:13]1)[S:9][CH3:10])[CH3:4].CN(C=[O:30])C>[NH4+].[Cl-]>[CH2:3]([O:5][C:6]([C:7]1[C:15](=[O:30])[C:16]2[C:17](=[CH:18][C:19]([Br:23])=[C:20]([F:22])[CH:21]=2)[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:8]=1[S:9][CH3:10])=[O:25])[CH3:4]
Reactant: CCOC(=O)C(Cc1cc(F)c(Br)cc1F)=C(NC1CC1)SC
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CCOC(=O)c1c(SC)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Temperature: 75 °C
Reaction time: 18 h

Procedure:
NaH (345 mg, 60% in mineral oil, 8.6 mmole, 1.05 equiv.) is added to a stirred solution of 2-(4-bromo-2,5-difluoro-benzyl)-3-cyclopropylamino-3-methylsulfanyl-acrylic acid ethyl ester (4, 3.46 g, 8.2 mmole) in DMF (anhydrous, 100 ml). The reaction mixture is stirred at 75° C. for 18 hours (TLC is used to indicate reaction completion). The reaction mixture is cooled, diluted with NH4Cl solution, and extracted with EtOAc. The organics are washed with brine (4×30 ml), dried over Na2SO4, and concentrated in vacuo to give 5 as a light yellow solid. This intermediate is used without further purification 1H NMR (CDCl3) indicated >98% purity). 1HNMR (CDCl3) δ: 8.09 (d, 1H), 7.90 (d, 1H), 4.35 (q, 2H), 3.22 (m, 1H), 2.49 (s, 3H), 1.3-1.5 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:20]=[O:21])[C:3]=1[CH3:30].CC(=CC)C.P([O-])(O)(O)=[O:37].[Na+].Cl([O-])=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[C:20]([OH:37])=[O:21])[C:3]=1[CH3:30]
Reactant: Cc1c(C(C=O)O[Si](C)(C)C(C)(C)C)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(O[Si](C)(C)C(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Reaction time: 8 h

Procedure:
A DCM solution (8.0 mL) of 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyl-oxy)acetaldehyde (0.65 g, 1.29 mmol) was combined with 2-methyl-2-butene (1.5 mL, 14.1 mmol), sodium dihydrogen phosphate (8.0 mL, 1.0 M) and sodium chlorite (1.37 g, 14.46 mmol) and stirred vigorously overnight. The mixture was diluted 200% with DCM, the acidity adjusted to pH<5 with 2 M NaHSO4 and extracted with DCM (3×20 mL). The extracts were combined dried and concentrated under vacuo. The crude mixture was observed to contain the desired carboxylic acid (0.741 g) according to 1H NMR analysis and was used without purification. 1H-NMR: (400 MHz, CD3OD): δ 8.35 (d, J=8.4 Hz, 1H); 7.58-7.51 (m, 3H); 7.46-7.44 (m, 1H); 7.39-7.33 (m, 1H); 7.31-7.22 (m, 2H); 5.33 (s, 1H); 2.72 (s, 3H); 0.825 (s, 9H); −0.03 (s, 3H); −0.26 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>>[I:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: Cc1cccc(C(=O)O)c1I
Solvent: O=S(Cl)Cl
Product: Cc1cccc(CO)c1I
Temperature: 50 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
Thionyl chloride [5 mL] was added to 2-iodo-3-methyl-benzoic acid (2.00 g, 7.63 mmol) at room temperature and heated to 50° C. for 1 hour. The solution was then cooled and evaporated. The crude residue was dissolved in ethyl acetate, washed with brine and dried with magnesium sulfate. The crude product was then dissolved in THF [5 mL] and a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature and stirred for 1 hour. Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.50 g, 26%) as a solid. 1H-NMR (CDCl3): δ 3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:30]([O:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:31])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
The amine was dissolved in anhydrous tetrahydrofuran (9 ml) under an atmosphere of nitrogen, at room temperature, and triethylamine (221 μl) was added dropwise. A solution of 4-nitrophenyl chloroformate (322 mg) in anhydrous tetrahydrofuran (9 ml) was then added, and the reaction mixture stirred for a further 3 h. After this time the undissolved solid was filtered off, washed with tetrahydrofuran, and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (2×50 ml) and the residue triturated with anhydrous ether to afford the title compound (425 mg) as a white solid. TLC (silica, petrol (60/80):ethyl acetate 2:1). Rf=0.3. 1H NMR (360 MHz, CDCl3) δ 1.22-2.10 (12H, m), 2.98 (1H, m), 3.45 (3H, s), 5.15 (1H, d, J=8.2 Hz), 6.89 (1H, d, J=9.2 Hz), 7.26-7.35 (4H, m), 7.49-7.60 (2H, m), 8.22 (2H, d, J=7.1 Hz).
Reaction SMILES: C([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5]1)C=C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:7]1([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:8]2[CH:6]1[CH2:5][NH:4][CH2:9]2
Reactant: C=CCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Temperature: 35 °C

Procedure:
A stirred mixture of N-[3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Example 56, 1.90 g, 6.19 mmol), tetrakis(triphenylphosphine)palladium (0) (71.8 mg, 62.1 mmol) and N,N-dimethylbarbituric acid (2.91 g, 18.6 mmol) in dichloromethane (15 ml) was degassed and then heated to 35° C. under nitrogen for 3 h. The solution was rapidly stirred with aqueous hydrochloric acid solution (2M, 40 ml) and the aqueous portion was separated, this process was repeated. The combined aqueous layers were washed with dichloromethane (7×50 ml), and then concentrated in vacuo to give the hydrochloride salt of the title compound as an off white solid (1.40 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:24])[CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])C)[CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.ClCC1[O:28][C:29]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][C:30]=2[N:31]=1>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:24])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:21][C:23]4[O:28][C:29]5[CH:35]=[CH:34][C:33]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[CH:32][C:30]=5[N:31]=4)[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: ClCc1nc2cc(-c3ccccc3)ccc2o1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCN(C(C)C)CC3)ccc2s1
Solvent: CN(C)C=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc5cc(-c6ccccc6)ccc5o4)CC3)ccc2s1
Temperature: 150 °C
Reaction time: 0 h

Procedure:
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ylpiperazinyl)propan-2-ol (0.035 g, 0.11 mmol) and DMF (1 mL) were placed in a Smith Process Vial™ (3 mL glass vessel) followed by the addition of 2-(chloromethyl)-5-phenyl-benzoxazole (0.027 g, 0.11 mmol). The vial was sealed and the mixture was heated in the Emrys Optimizer™ microwave at 150° C. for 300 sec, fixed hold time on, absorption level normal, pre-stirring 10 s. It was then cooled to room temperature, evaporated under reduced pressure and the residue was purified by flash chromatography (3% MeOH in CH2Cl2) to yield (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[(5-phenylbenzoxazol-2-yl)methyl]piperazinyl}propan-2-ol as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:12]CC)=[N:9]2)=[CH:4][C:3]=1[N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]1.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(Cl)cc2nc1OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Yield: 145.1 %

Procedure:
To a solution of the compound of Example 35 (740 mg, 1.97 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (5 ml), and the mixture was refluxed for 16 hours, attaching Dean-Stark refluxing apparatus equipped with molecular sieves 4A. After cooling, the precipitated crystals were collected by filtration, washed with ethanol and then dried under reduced pressure, thereby obtaining 994 mg of title compound as light brown powder. The yield was quantitative.
Reaction SMILES: [C:1]([NH:4][C:5]([C@@H:17]1[CH2:20][C@H:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:36][C:37]1([CH3:44])[C:41]([CH3:43])([CH3:42])[O:40][BH:39][O:38]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([C@@H:17]1[CH2:18][C@H:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:20]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:39]1[O:40][C:41]([CH3:43])([CH3:42])[C:37]([CH3:44])([CH3:36])[O:38]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@H]1C[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)C1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@H]1C[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
After stirring for 30 min, a solution of cis-tert-butyl 3-(2-acetamido-1-(tert-butylamino)-1-oxohex-5-en-2-yl)cyclobutyl(benzyl)carbamate (5.34 g, 10.5 mmol), chloro-1,5-cyclooctadiene iridium(I) dimer (212 mg, 0.32 mmol, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (252 mg, 0.63 mmol, 6 mol %) in dichloromethane (50 mL) was cooled to 0° C. and carefully treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.1 mL, 21.1 mmol, 2 eq) over 5 min. After slowly warming to room temperature and stirring overnight, the reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave cis-tert-butyl 3-(2-acetamido-1-(tert-butylamino)-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)cyclobutyl(benzyl)carbamate (4.8 g, 7.83 mmol, 74%). ESI MS found for C34H56BN3O6 m/z [614.2 (M+1), 636.2 (M+23)].
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
(R)-2-Acetylamino-3-methoxypropionic acid (8.06 g, 0.05 mol) was dissolved in tetrahydrofuran (80 mL). Isobutyl chloroformate (7.8 mL, 0.06 mol) was added at −10° C. within 10 minutes, followed by 4-methylmorpholine (6.6 mL, 0.06 mol), and the mixture was stirred at −10° C. for 40 minutes. A solution of benzylamine (6.55 mL, 0.06 mol) in tetrahydrofuran (10 mL) was then added at −10° C. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue dissolved in dichloromethane. The solution was successively washed with water (30 mL), 1M HCl (30 mL), 5% sodium hydrogencarbonate solution (30 mL) and again with water (30 mL). The solvent was evaporated and the residue crystallized in ethyl acetate to afford the title compound (7.09 g, 57%). LCMS analysis: 98.0%.
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](CC)[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.Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[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[C:9](=[N:11][N:12]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=C(CBr)c1ccccc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-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 2-bromo-1-phenylethanone and isolated as light-green solid (9.5 mg, 55%). MS (m/e): 401.4 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1>>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[N:19][C:18]([N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH2:10][CH2:9]4)[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: Cl
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared according to the procedure as described in Example 1, Method B, reacting 1-(piperidin-4-yl)indoline HCl salt and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine.