Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C(OC([N:37]1[CH2:40][CH:39]([N:41]2[CH:45]=[C:44](I)[CH:43]=[N:42]2)[CH2:38]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[NH:37]1[CH2:40][CH:39]([N:41]2[CH:45]=[C:44]([C:18]3[CH:19]=[C:20]4[C:12]([CH:10]([C:3]5[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=5[Cl:1])[CH3:11])=[CH:13][NH:14][C:15]4=[N:16][CH:17]=3)[CH:43]=[N:42]2)[CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100.0 mg, 0.230 mmol), 3-(4-iodopyrazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (88.3 mg, 0.253 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (95.3 mg, 0.689 mmol) and 4:1 dioxane/H2O (8 mL) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and water. The organic layer was concentrated in vacuo, redissolved in dioxane, and 4M HCl in dioxane (1 mL) was added. The solution was heated to 45° C. for 3 h. The solvents were removed on the corrosive pump, and the material was dry-loaded onto silica gel for column chromatography, eluting with 3-6% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.88 (d, J=7.3 Hz, 3 H), 3.90-3.98 (m, 2 H), 4.08-4.15 (m, 2 H), 5.20-5.34 (m, 2 H), 7.18 (t, J=8.6 Hz, 1 H), 7.36 (d, J=1.3 Hz, 1 H), 7.36-7.48 (m, 2 H), 7.65 (s, 1 H), 7.95 (s, 1 H), 8.32 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 430.10 (100) [MH+]. HPLC: tR=2.25 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
4-bromo-2-chloro-5-fluorobenzoic acid (Apollo PC9723, 5 g; 19.73 mmol; 1 eq.) was dissolved in MeOH (100 mL). The solution was cooled down to 0° C. SOCl2 (4.29 mL; 59.18 mmol; 3 eq.) was added dropwise (addition took 15 min and IT increased to 9° C.). The reaction mixture was stirred at RT for 2 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO3(30 mL) and brine (30 mL), dried over MgSO4 and concentrated under vacuum affording the title compound as a white powder (5.26 g, 99%), 1H NMR (DMSO-d6, 300 MHz) δ 8.10-8.08 (d, J=6.28 Hz, 1H), 7.86-7.83 (d, J=8.63 Hz, 1H), 3.87 (s, 3H). HPLC (Method A) Rt 4.32 min (Purity: 99.6%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6].[ClH:12]>C(O)C>[ClH:12].[SH:3][C:2]1[N:4]=[C:9]([CH3:10])[CH:8]=[C:5]([CH3:6])[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)nc(S)n1

Procedure:
Thiourea (76 g, 1.0 mole) was suspended in a solution of 120 g (1.2 moles) of acetylacetone in 2,500 ml of ethanol. The resulting suspension was mixed with 250 ml of concentrated hydrochloric acid, and then reacted under reflux for 2 hours. After completion of the reaction, the reaction liquid was cooled, whereby beautiful yellow needle-like crystals of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride were formed. The reaction liquid was allowed to stand for a day to deposit sufficiently the crystals, which were then recovered by filtration and dried to obtain 140 g of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride in yield of 80 %.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21]([CH2:24][CH3:25])CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:14]([NH:8][C:6](=[O:5])[C@H:24]([CH2:25][C:10]2[CH:18]=[CH:17][CH:13]=[CH:12][CH:11]=2)[NH2:21])=[O:16])[CH2:17][CH2:18]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(t-butoxycarbonylaminomethyl)benzoic acid (3.77 g), L-phenylalamine amide hydrochloride (3.01 g), triethylamine (2.25 g) and dry dichloromethane (100 ml) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.16 g) was added, under ice-cooling, and after cooling for 2 hours, the mixture was stirred under room temperature for 2 hours. The solvent was evaporated under a reduced pressure, water was added to the residue to effect powdering, and the powder was collected by filtration. The powder was washed with 10% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, and then water, in this order, followed by drying, to give N-[4-(t-butoxycarbonylaminomethyl)benzoyl]-L-phenylalamine amide (I) (4.41 g). The structure was confirmed by NMR spectrum.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C1(C)C(C)=CC=CC=1.N([C:24]1[NH:25][CH2:26][CH2:27][N:28]=1)[N+]([O-])=O.C1C=CC=CC=1>CC(C)=O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([OH:11])[CH2:2][NH:1][C:24]2[NH:28][CH2:27][CH2:26][N:25]=2)=[CH:5][CH:6]=1
Reactant: NCC(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: OC(CNC1=NCCN1)c1ccc(F)cc1
Temperature: 160 °C

Procedure:
To a solution of 6.5 parts of α-(aminomethyl)-p-fluorobenzyl alcohol in 8 parts of xylene are added 5.2 parts of 2-(nitramino)-2-imidazoline. The mixture is heated in an oil-bath to about 160°C. till gas-evolution is ceased (about 15 minutes). The reaction mixture is cooled and treated with benzene and acetone. The product is sucked off and crystallized from 4-methyl-2-pentanone, yielding p-fluoro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 153.4°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(#N)C>[CH2:38]([O:37][C:35]([C:34]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:33]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)ccc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 67.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.23 g (0.54 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.2, with 0.21 g (1.07 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 192 mg of the expected product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:12]1=[O:27].[OH-].[Na+]>>[Cl:26][C:22]1[CH:21]=[C:20]([N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:12]2=[O:27])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 9.3 g. of 8-[3-(3-chlorophenyl)-2-oxo-benzimidazolin-1-yl]-caprylic acid methyl ester and 2.56 g. of NaOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH3:11][Si:12]([CH2:15]Cl)([CH3:14])[CH3:13]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)CCl
Reactant: COc1ccccc1CN
Solvent: CC#N
Product: COc1ccccc1CNC[Si](C)(C)C

Procedure:
A mixture of 2-methoxybenzylamine (25 g, 182.2 mmol) and trimethylsilylmethyl chloride (11.2 g, 91.1 mmol) in acetonitrile (140 ml) was refluxed overnight. Then the mixture was concentrated under vacuum at 70° C. with a rotary evaporator to remove all volatiles. The white residue was mixed with n-heptane (250 ml) and filtered over a glass filter. The salt residue was washed with n-heptane (2×25 ml). The combined heptane filtrates were concentrated under vacuum to give the crude product 2-methoxy-N-[(trimethylsilyl)methyl]benzenemethanamine as a clear oil (21.5 g; >100%) in quantitative yield. The product (92% pure according to GC-MS) was used without further purification.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH:1]1([CH2:7][C:8]([NH:59][C:57]2[S:56][C:46]3[C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CC3CCCCC3)nc12

Procedure:
From cyclohexylacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 391 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.C(OC([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]([C:55]([O:57]C(C)(C)C)=[O:56])[NH2:54])=O)(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:54][C@@H:53]([C:55]([OH:57])=[O:56])[CH2:52][CH2:51][CH2:50][CH2:49][NH2:48])=[O:36])=[O:32])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CCCCN)C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.0177 g, 0.032 mmol tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (0.0141 g, 0.042 mmol), N-methylmorpholin (0.0106 ml, 0.096 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.013 g, 0.042 mmol) was added and the mixture was stirred for 2 h. Additional tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (0.004 g, 0.012 mmol) was added and after 0.5 h. TBTU (0.008 g, 0.025 mmol) was added and the mixture was stirred for additional 10 minutes. Trifluoroacetic acid (0.65 ml) was added and after 3 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using a gradient of 5-100% MeCN in 0.15% 1M ammonium acetate buffer as eluent. After removing the solvents under reduced pressure, the intermediate (M/z 681.4) was dissolved in methanol (3 ml). NaBH4 (0.008 g, 0.211 mmol) was added and when the reaction was complete a few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.020 g (91%) of the title product was obtained. NMR (500 MHz, CD3COOD) 1.41-1.52 (m, 2H), 1.58-1.78 (m, 3H), 1.90-2.02 (m 1H), 2.86-3.08 (m, 4H), 3.76 (s, 1.5H), 3.77 (s, 1.5), 3.90-4.06 (m, 3H), 4.48 (dd, 1H), 4.60-4.62 (m, 2H), 4.73-4.78 (m, 1H), 4.83-4.89 (m, 1H), 6.80-6.84 (m, 2H), 6.98-7.08 (m, 4H), 7.21-7.31 (m, 4H), 7.31-7.36 (m, 2H), 8.20 (d, NH), 8.54 (t, NH).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16](O)=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:30]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[CH:1]1([CH2:6][CH:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16]([NH2:30])=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCOCC1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid (100 mg, 0.24 mmol) in dry tetrahydrofuran (3 mL) under argon was treated with N-methylmorpholine (0.04 mL, 0.36 mmol) followed by iso-butylchloroformate (50 μL, 0.36 mmol). The reaction was stirred at 25° C. for 2 h, after which time, a concentrated aqueous ammonium hydroxide solution (0.2 mL) was added. The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then treated with water (5 mL), and the tetrahydrofuran was concentrated in vacuo. The product was then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 chloroform/methanol) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid amide (68 mg, 67%) as a white solid: mp 155-160° C.; EI-HRMS m/e calcd for C19H23N3O4S2 (M+) 421.1130, found 421.1135.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]2[C:2]3=[N:3][CH:4]=[N:5][C:6]([O:10][C:11]4[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=4)=[C:7]3[CH:8]=[N:32]2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Reactant: Cc1ncccc1Oc1ncnc(Cl)c1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 38.3 %

Procedure:
A mixture of 4-chloro-6-(2-methyl-pyridin-3-yloxy)-pyrimidine-5-carbaldehyde (Intermediate 18; 515 mg, 2.1 mmol) and 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 9; 688 mg, 3.2 mmol) in toluene (5 mL) was heated at reflux overnight. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phases were evaporated and purified on an Isco 40 g column, eluting with 0-3% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (330 mg, 38%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[CH:16][N:15](C3CCCCO3)[N:14]=2)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH3:3][CH:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][NH:15][N:14]=2)[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=1)[CH3:2]
Reactant: CC(C)c1cc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNCCN(C)Cc1c[nH]nc1-c1cc(C(C)C)cc(C(C)C)c1
Yield: 113.1 %

Procedure:
A solution of tert-butyl N-[2-[([3-(3,5-diisopropylphenyl)-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl)(methyl)amino]ethyl]-N-methylcarbamate (180 mg, 0.35 mmol, 1.00 equiv) in a saturated hydrogen chloride solution in 1,4-dioxane (5 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was triturated with 1×50 mL of ether to give 130 mg (92%) of ([3-[3,5-bis(propan-2-yl)phenyl]-1H-pyrazol-4-yl]methyl)(methyl)[2-(methylamino)ethyl]amine as a light yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.25-8.22 (m, 1H), 7.31 (s, 1H), 7.27 (s, 2H), 4.70-4.37 (m, 2H), 3.60-3.35 (m, 4H), 3.04-2.94 (m, 2H), 2.72 (s, 3H), 2.71 (s, 3H), 1.31 (d, J=7.2 Hz, 12H) ppm. LCMS (method H, ESI): RT=1.34 min, m/z=329.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH:34][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][NH:8]3)=[O:18])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=351.2.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(=O)OC(CCCO)COc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
A solution of p-toluenesulfonyl chloride (42.0 g., 0.22 mole) in pyridine (100 ml.) is cooled in an ice bath while 4-acetoxy-5-(4-fluorophenoxy)-1-pentanol (49.7 g., 0.193 mole) is added dropwise with stirring during 40 minutes. The ice bath is replaced by a cool (20°) water and stirring is continued for 2 hours. The mixture is then poured into 500 ml. of water. The oily product is taken up in ether, washed with 2N hydrochloric acid and water and dried over sodium sulfate. The solvent is distilled in vacuo to leave 73.5 g. (93%) of the crude title compound as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23]4([C:25]([F:27])([F:26])[CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23]4([C:25]([F:27])([F:26])[CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-4-((1,1-difluoro-6- methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoate (0.426 g, 1.00 mmol) and anisole (0.155 mL, 1.50 mmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (1.06 mL, 13.5 mmol). The reaction mixture was stirred at 0° C. for 3 hours before being quenched with water (5 mL). The reaction was diluted with dichloromethane (20 mL) and washed with water (4×10 mL) until the last wash was neutral as monitored by pH paper. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (0.353 g, 95%) as a white solid: MS (ES−) m/z 367.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][C:25]1([CH3:38])[CH2:30][CH:29]([N:31]2[CH2:34][CH2:33][CH:32]2[C:35]([O-])=[O:36])[CH2:28][CH2:27][O:26]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([CH:32]2[CH2:33][CH2:34][N:31]2[CH:29]2[CH2:28][CH2:27][O:26][C:25]([CH3:38])([CH3:24])[CH2:30]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC1(C)CC(N2CCC2C(=O)[O-])CCO1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: CC1(C)CC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CCO1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate 20H carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (quant.). MS ISP (m/e): 549.3 (100) [(M+H)]]+.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)[C:17]([Cl:36])=[CH:16]1.O>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[NH:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH:33]3[CH2:34][CH2:35]3)[CH:22]=2)[C:17]([Cl:36])=[CH:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(Cl)cn(CCN)c2c1)C1CC1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)NCCn1cc(Cl)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine (80 μL) and methyl chloroformate (38 μL) were added to a solution of tert-butyl {[1-(2-aminoethyl)-3-chloro-1H-indol-6-yl]methyl}cyclopropylcarbamate (120 mg) in chloroform (4.0 ml) under ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform/methanol=100/1 to 20/1) to give methyl[2-(6-{[(tert-butoxycarbonyl)(cyclopropyl)amino]methyl}-3-chloro-1H-indol-1-yl)ethyl]carbamate (106 mg) as a pale yellow oil.