Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C1COCC1>[O:16]=[C:12]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([O:31][C:30]([F:29])([F:41])[F:42])[CH:33]=4)[CH:19]=[CH:18][CH:17]=3)[C:15]=2[N:14]=[CH:13]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Method G1: 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (43 mg, 0.169 mmol) and diisopropylethylamine (44 μL, 0.254 mmol) were mixed in dry THF (5.0 mL) and 3-trifluoromethoxybenzoyl chloride (57 mg, 0.254 mmol) was added. This mixture was heated to reflux for 17 h. After cooling at RT, the solvent was removed in vacuo. The obtained oily residue was dissolved in DCM and washed with water and dried over MgSO4. After evaporation of DCM, the residue was retaken in Et2O, triturated and filtered off to afford the title compound as a white solid (45 mg, 60%).
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])[CH3:5].[Cl-].[NH4+].[C:15](OCC)(=O)C>O1CCCC1>[OH:6][C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:15])[CH3:5]
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1

Procedure:
To methylmagnesium bromide (a 0.96 mol/L solution in tetrahydrofuran, 6.26 mL, 5.97 mmol), a solution of 3-acetylpyridine (362 mg, 2.99 mmol) in tetrahydrofuran (3.6 mL) was slowly added under a nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 1. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby 3-(1-hydroxy-1-methylethyl)pyridine (Compound DG) (415 mg, yield: quantitative) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](OC)=[O:13])=[CH:2]1.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:13][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Indolepropionic acid (5 g) was dissolved in MeOH (50 mL) and treated with conc. HCl (5 mL). The solution was stirred overnight before the solvent was removed under reduced pressure to provide methyl 3-indolepropionate in quantitative yield. Crude methyl 3-indolepropionate (4.70 g, 23.2 mmol) was dissolved in THF (50 mL), cooled to 0° C., and treated with DIBAL-H (69.5 mL, 69.5 mmol). The reaction mixture was stirred for 2 h at 0° C. and then quenched by the slow addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with 1:1 ethyl acetate/hexane, afforded the 3-(3-hydroxypropyl)indole as a yellow solid. 1H NMR (200 MHz, DMSO-d6) δ 7.48 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15–6.92 (m, 4H), 4.40 (t, J=6.0 Hz, 1H), 3.55 (t, J=6.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 1.92–1.76 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:12]([S:16]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1cccc2cccnc12
Yield: 92.2 %

Procedure:
The reaction of 5.0 g (0.0347 mole) of 8-aminoquinoline with 5.43 g (0.0347 mole) of n-butanesulfonyl chloride was carried out in 10 ml of pyridine at room temperature. After 2 hours from the start of the reaction, the reaction mixture was washed with water, extracted with diethyl ether, purified by column chromatography and concentrated to give 10.32 g (0.032 mole, 92%) of 8-(n-butylsulfonamido)quinoline. Then, 5.0 g (0.019 mole) of the 8-(n-butylsulfonamido)quinoline, 2.12 g (0.019 mole ) of zinc chloride and 4.76 g (0.047 mole) of triethylamine were suspended in 30 ml of ethanol and allowed to react at room temperature. After 3 hours, the separated yellow powder was filtered, washed with ethanol and purified by column chromatography to give 8.62 g (91.0%) of Compound N as yellow crystals. The maximum PL wavelength of this compound in chloroform was 510 nm.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:15]Br>C(O)(=O)C>[Br:15][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: BrBr
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2c(Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid (3.0 g, 15.9 mmol) was suspended in acetic acid (40 mL) and with vigorous stirring a solution of bromine (817 μL, 15.9 mmol) in acetic acid (10 mL) was added drop wise during 30 minutes. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying in vacuo afforded 3.74 g (88%) of 4-bromo-3-hydroxynaphthalene-2-carboxylic acid as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[Cl:57][C:58]1[CH:69]=[CH:68][CH:67]=[CH:66][C:59]=1[O:60][CH:61]1[CH2:65][CH2:64][NH:63][CH2:62]1>CN(C=O)C>[Cl:57][C:58]1[CH:69]=[CH:68][CH:67]=[CH:66][C:59]=1[O:60][CH:61]1[CH2:65][CH2:64][N:63]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:62]1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Reactant: Clc1ccccc1OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)C1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 43.4 %

Procedure:
DIPEA (167 mg, 1.3 mmol) followed by HOBt (48 mg, 0.35 mmol) and EDCI (124 mg, 0.64 mmol) were added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (80 mg, 0.32 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 72) (75.7 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from a mixture of DCM and hexane afforded 60 mg (43.4% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 427. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.2 (d, 1H), 8.75 (d, 1H), 8.6 (q, 1H), 8.4 (m, 1H), 7.7 (q, 1H), 7.5-7.4 (m, 1H), 7.4-7.2 (m, 2H), 7.06-6.96 (m, 1H), 5.3-5.1 (d, 1H), 4.25-4.0 (m, 2H), 4.0-3.6 (m, 4H), 3.5-3.4 (m, 1H), 2.3-2.2 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[O:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=2)[N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][C:18]=1[CH3:32]>>[C:13]([C:11]1[O:12][C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:29]([C:24]3[N:25]=[C:26]([CH3:28])[O:27][C:23]=3[C:20]3[CH:21]=[CH:22][C:17]([I:16])=[C:18]([CH3:32])[CH:19]=3)=[O:30])[CH:6]=[N:5]2)=[CH:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Reactant: CC(=O)c1ccc(Cn2ncc(N)n2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccc(I)c(C)c3)n2)o1

Procedure:
Following general procedure A, starting from 1-(5-((4-amino-2H-1,2,3-triazol-2-yl)methyl)furan-2-yl)ethanone and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.12 min; [M+H]+=549.20.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[C:17]1(C)C=CC=CC=1.C1COCC1.[BH4-].[Na+]>>[C:1]([C:5]1[N:6]=[CH:7][C:8]([CH:9]([NH2:10])[CH3:17])=[C:11]([CH3:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)ncc1C#N
Reactant: Cc1ccccc1
Agent: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)ncc1C(C)N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of [1-(6-tert-butylpyridin-3-yl)ethyl]amines starting from 6-tert-butyl-4-methylnicotinonitrile (intermediate 24) (250 mg, 1.43 mmol), MeMgBr 1.4 M 75/25 toluene/THF (2.55 ml, 3.58 mmol) and NaBH4 (135 mg, 3.58 mmol). Purified by normal phase chromatography with 15 to 20% MeOH/CH2Cl2. (Yield 55 mg, 20%). 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 1.42 (d, J=6.64 Hz, 3 H) 2.35 (s, 3 H) 4.34 (q, J=6.64 Hz, 1 H) 7.07 (s, 1 H) 8.60 (s, 1 H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=12.[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[CH:9][N:4]2[C:3]([I:14])=[CH:2][N:1]=[C:5]2[CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of methyl imidazo[1,2-a]pyridine-7-carboxylate (1 g, 5.68 mmol) in DMF (30 ml) was added N-iodosuccinimide (1.53 g, 1.2 equiv) and the resulting mixture was stirred for 2 h at room temperature. The thin brown slurry was diluted with water, 10% w/v sodium thiosulfate and sodium carbonate (1M) and extracted with CH2Cl2. The aqueous was further extracted with CH2Cl2. The combined organic phases were washed with brine (280 ml), dried (MgSO4) and concentrated in vacuo to give a brown residue. The residue was triturated with ether, filtered and the solid was washed ether (2×50 ml) and dried on the filter to give the product as a white solid (0.81 g). 1H NMR (400 MHz, Me-d3-OD): 8.44 (1H, d), 8.25 (1H, s), 7.88 (1H, s), 7.61 (1H, dd), 3.95 (3H, s). MS: [M+H]+ 303.
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(OC)(=O)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:53][O:54][C:55]([C:57]1([NH:61][C:62]([C:64]2[CH:72]=[C:71]3[C:67]([C:68]([CH:75]4[CH2:79][CH2:78][CH2:77][CH2:76]4)=[C:69](Cl)[N:70]3[CH3:73])=[CH:66][CH:65]=2)=[O:63])[CH2:60][CH2:59][CH2:58]1)=[O:56]>[Zn+2].[Br-].[Br-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[CH3:53][O:54][C:55]([C:57]1([NH:61][C:62]([C:64]2[CH:72]=[C:71]3[C:67]([C:68]([CH:75]4[CH2:76][CH2:77][CH2:78][CH2:79]4)=[C:69]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:70]3[CH3:73])=[CH:66][CH:65]=2)=[O:63])[CH2:60][CH2:59][CH2:58]1)=[O:56]
Reactant: Brc1ccccn1
Reactant: COC(=O)C1(NC(=O)c2ccc3c(C4CCCC4)c(Cl)n(C)c3c2)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: COC(=O)c1ccccc1
Product: COC(=O)C1(NC(=O)c2ccc3c(C4CCCC4)c(-c4ccccn4)n(C)c3c2)CCC1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of i-PrMgCl in THF (10 mL, 20 mmol) was added 2-bromopyridine (1.93 g, 20.2 mmol) at room temperature in one portion. The mixture was stirred at 35° C. for 0.5 h. To the deep-red solution was added ZnBr2 (4.50 g, 20 mmol) under argon and the resulting mixture was stirred at 70° C. for 0.5 h to obtain a thick white slurry. 1-Methyl-2-pyrrolidinone (20 mL) was added and followed by methyl benzoate (2.5 mL, 20 mmol). The mixture was stirred at 70° C. for 0.5 h. The mixture was cooled to room temperature. Palladium acetate (56.1 mg, 0.25 mmol), 2-dicyclohexylphosphinobiphenyl (350.5 mg, 1 mmol) and 1-[(2-chloro-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid methyl ester (1.944 g, 5 mmol) were added. The mixture was stirred at 90° C. until no starting material was left (˜4 h) as monitored by HPLC. The ratio of the coupling product and the starting material was estimated to be 78/22 by HPLC.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3C)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.CN(C)C=O.[O:44]1[C:48]([C:49](O)=[O:50])=[CH:47][N:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][N:20]([C:49]([C:48]4[O:44][CH:45]=[N:46][CH:47]=4)=[O:50])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1cnco1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnco2)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (71 mg, 0.18 mmol) and N,N-diisopropylethylamine (6.0E1 uL, 0.34 mmol) were dissolved in N,N-Dimethylformamide (1.0 mL, 13 mmol). Oxazole-5-carboxylic acid (30.0 mg, 0.265 mmol) 1-hydroxybenzotriazole (27.8 mg, 0.206 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (49.9 mg, 0.260 mmol) were weighed out into a vial, and the solution of the amines was added, then the reaction stirred overnight. The resultant precipitate was removed by filtration and washed with H2O. The resulting solid was purified by reverse phase HPLC: 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 4.98-4.54 (m, 2H), 4.19-4.07 (m, 1H), 4.00-3.54 (m, 7H), 3.48-3.37 (m, 1H), 3.15-3.08 (m, 2H), 2.92-2.65 (m, 2H), 1.26 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H) LC-MS: m/z=+492.2 (M+H)+.
Reaction SMILES: NN.[C:3]1([C:9]([N:22]=[C:23]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[OH:27]>C1COCC1>[CH3:23][N:22]1[CH2:9][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:7][OH:27]
Reactant: CCO
Reactant: O=C=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CO
Reaction time: 8 h

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the procedure described above except 3 rounds of crystallization were performed. To a mixture of (±)-1-methyl-2-piperidinemethanol (95.6 g, 740 mmol) in EtOH (840 mL) was added dibenzoyl-L-tartaric acid (255 g, 711 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to provide 79.6 g. This process was repeated: (2) EtOH (335 mL) provided 50.4 g. (3) EtOH (345 mL) provided 35 g. The resulting salt was treated with 3M HCl (134 mL) which was heated to induce it to dissolve. The still warm solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 6 g of the alcohol. This alcohol (6 g, 46.7 mmol) was suspended in CH2Cl2 (100 mL) and SOCl2 (6.8 mL, 93.3 mmol) added dropwise. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt (5.98 g) was dissolved in EtOH (100 mL) and treated with NH2NH2 (19.5 mL, 405 mmol) and heated to reflux for 3 h. Half the solvent was removed, the residue extracted with ether and the extracts dried and concentrated to give 4.55 g of a crude oil. This crude hydrazine (2.01 g, 14.06 mmol) was dissolved in THF (100 mL) and triphenylmethylisocyanate (4.0 g, 14.1 mmol) was added slowly. The solution was then stirred overnight and the solvent removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH/OH) to provide 350 mg of the desired product. 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.30–1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H), 7.12–7.32 (m, 15H), 8.02 (s, H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[C:7](=[C:8]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]4)[N:9]=[CH:10][N:11]=3)[C:6]1=2)(=[O:3])[NH2:2].Cl.[BH3-][C:34]#N.[Na+]>ClCCl>[CH3:34][N:24]([CH3:25])[CH:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:23][CH2:22]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate (187 mg, 0.42 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrogen chloride (12 M, 1 mL). The resulting solution was stirred for 2 h at room temperature. After evaporation, the residue was dissolved in CH3OH (10 mL) and HCHO (1.5 mL) was added. The resulting solution was stirred for 1 h at room temperature. To the above solution was added NaBH3CN (79 mg, 1.26 mmol, 3.00 equiv). The resulting solution was allowed to react, with stirring, overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined. The crude product (100 mg) was purified by preparative HPLC under the following conditions: Column: Xbridge Prep C18, 5 μm, 19*150 mm; mobile phase, water (with 50 mL NH4CO3) and CH3CN (10.0% CH3CN up to 32.0% in 10 min, up to 95.0% in 1 min, down to 10.0% in 2 min); UV detection at 254 nm. This procedure afforded 50 mg (32%) of 2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. MS (ES): m/z 374 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.35-1.60 (m, 4H), 1.95-2.04 (m, 2H), 2.09-2.10 (m, 2H), 2.28-2.38 (m, 7H), 2.40-2.45 (m, 3H), 2.68-2.80 (m, 1H), 2.89-2.30 (m, 1H), 3.05-3.15 (m, 1H), 4.05-4.15 (m, 1H), 3.87 (dd, J=14.1, 6.3 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]([CH3:42])[CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (250 mg, 62%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10](S(C)(=O)=O)=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3].[C-:34]#[N:35].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10]([C:34]#[N:35])=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3]
Reactant: [C-]#N
Reactant: C=CCOC(=O)c1c(Cl)nc(S(C)(=O)=O)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)c1c(Cl)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic procedure as described in Ref. Example 2, a solution of 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methanesulfonylpyrimidine-5-carboxylic acid allyl ester (1.8 mmol) in CH2Cl2 (5 mL) is treated with a solution of NaCN (2.2 mmol) and tetra-n-butylammonium bromide (0.10 mmol) in water (2 mL) for 0.5 h. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester as colorless oil; 1H-NMR (CDCl3), δ: 1.12-1.73 (9H, m), 1.48 (9H, s), 2.68 (2H, brt), 4.05-4.09 (2H, m), 4.55 (2H, t), 4.87 (2H, dt), 5.33-5.37 (1H, m), 5.41-5.47 (1H, m), 5.98 (1H, ddt).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].C(=O)(O)[O-].[Na+].[C:13]([O:18][CH:19]([O:21][C:22](OC1CC(=O)NC1=O)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]>O.C(#N)C.C(OCC)C>[C:13]([O:18][CH:19]([O:21][C:22]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6])=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: NCCCP(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NCCCP(O)O)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropylphosphonous acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) is added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction is stirred at ambient temperature for 16 h. The reaction mixture is diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (31) as a white solid.