Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:33]>O1CCOCC1>[NH2:33][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=1
Reactant: Cc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)c1C#N
Reactant: N
Solvent: C1COCCO1
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
(S)-4-Methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (15 mg, 0.033 mmol) in dioxane (2 mL) was combined with ammonia in dioxane 0.5 M (0.198 mL, 0.099 mmol) to give a yellow solution, which was stirred for 6 hours at room temperature. The product was purified by LC/MS using a 20-45% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to give a formic acid salt of the title compound as a white solid (2 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.47 (m, 3 H), 2.17-2.28 (m, 3 H), 2.70-2.85 (m, 2 H), 2.96-3.13 (m, 2 H), 3.67-3.92 (m, 8 H), 5.82-5.97 (m, 1 H), 6.45-6.59 (m, 1 H), 6.87-6.98 (m, 2 H), 7.52-7.62 (m, 1 H), 7.82-7.91 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H24N8O3S, 393.4; found 393.4.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.Cl[C:20]([O:22][CH3:23])=[O:21].CC(C)([O-])C.[Li+]>C(OC(C)C)(C)C>[CH3:23][O:22][C:20](=[O:21])[NH:14][C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][CH3:16]
Reactant: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Product: CC[C@H](CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 2 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (6094 g, 23.42 mol), isopropyl ether (30 L) and methyl chloroformate (2.7 kg, 29 mol). The resulting slurry was cooled to 2° C. The reaction tank was then charged with lithium t-butoxide solution (18-20% in THF, 24.6 kg, ˜58 mol) at such a rate as to maintain the internal temperature below 10° C. and preferably at a temperature of about 5° C. Ten minutes after addition of base was complete, the reaction was quenched by the addition of 1.5 M hydrochloric acid (36 L). The aqueous layer was removed, and the organic phase extracted with saturated NaCl/water solution (10 L). The aqueous layer was removed and the organic phase was concentrated by distillation under vacuum and at a temperature of about 50° C. until the volume was reduced to about 24 L. Cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50° C. under vacuum until the volume of solution in the vessel was reduced to 24 L. A second portion of cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50° C. under vacuum until the volume of solution in the vessel was reduced to 24 L. While holding the temperature at 50° C., the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid methyl ester and allowed to granulate while stirring for 2 hours. The solution was then cooled slowly (over 1.5 hours) to room temperature and allowed to granulate while stirring for 15 hours. The mixture was filtered. The resulting solids were rinsed with cyclohexane (10 L) and dried under vacuum at 40° C. to afford 7504 g of the title compound (94%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22].CCN(C(C)C)C(C)C>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CC(N)c1ccc(S(C)(=O)=O)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1ccc(S(C)(=O)=O)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-methanesulfonyl-phenyl)-ethylamine and DIEA to give 2-[1-(4-methanesulfonyl-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 438 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](COC)[C:22]3[N:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:20])=[O:19])=[C:13]([F:31])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C=C(Cl)C=CC=2OC2C(Cl)=CC(S(/N=C3/N(COC)N=CC=C/3)(=O)=O)=C(F)C=2)C=CN=1.FC(F)(F)C(O)=O.CO.Cl.O>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:19])=[O:20])=[C:13]([F:31])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COCN(c1cccnn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: COCn1nccc/c1=N\S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cccnn3)cc2Cl)ccn1
Reaction time: 24 h

Procedure:
4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamide and 4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide, (Preparation 875, 93 mg, 0.17 mmol) in trifluoroacetic acid (1 mL, 10 mmol) was stirred for 24 hours. The reaction mixture was concentrated and the residue was taken in methanol (1 mL, 20 mmol) and 2 M of hydrogen chloride in water (1 mL, 2 mmol). After stirring for two days, the reaction mixture was concentrated and the residue liophilized from acetonitrile-water to give 76 mg of product as a hydrochloride salt.
Reaction SMILES: [N:1]#[C:2]Cl.[S:4]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:5]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:2]([C:11]1[N:10]([CH2:9][C:6]2[CH:7]=[CH:8][S:4][CH:5]=2)[CH:14]=[CH:13][N:12]=1)#[N:1]
Reactant: N#CCl
Reactant: c1cn(Cc2ccsc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nccn1Cc1ccsc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 250 ml, 4-neck flask equipped with a nitrogen bubbler, gas inlet tube, thermometer and septum, add 100 ml acetonitrile and bubble cyanogen chloride (15 g, 0.24 mol) into the acetonitrile. Cool the solution in an ice bath and add 8.2 (0.05 mol) 1-(3-thienylmethyl)-1H-imidazole. After the colorless solution turns yellow-orange and about 1 hour after an orange precipitate forms, cool the slurry to -20° C., slowly add 42 ml (0.3 mol) of triethylamine, holding the temperature below 0° C. After 1 hour at room temperature, pour the reaction onto 600 ml saturated NaHCO3 and extract with ether (3×150 ml). Dry and combine organic layers to obtain tan oil. The oil is purified via Kugelrohr distillation to obtain a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 20 °C
Yield: 75.3 %

Procedure:
The ester 56a (210 mg, 0.356 mmol) in dichloromethane (0.5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (0.5 ml), stirred and warmed to 20° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated (×3). The residue was triturated with ethyl acetate and diluted with ether to afford the title compound 162 mg (85%) as a colorless solid: m.p. 165-8° C. (decomposition); [α]D23 −38.8° (c 0.1, CH3OH); IR (KBr) 3332, 3275, 1723, 1658, 1649, 1597, 1581, 1562, 1526, 1432, 1385, 1258, 1218, 1206; 1H NMR (d6-DMSO) δ 8.96 (1H, d, J=7.3), 8.34 (1H, s), 7.85 (1H, dd, J=7.3), 7.58 (3H, m), 7.35 (5H, m), 6.29 (1H, t, J=7.3), 5.26 (2H, m), 5.15 (2H, s), 4.69 (3H, m), 2.75 (2H, m). Anal. Calcd. C27H23N3O9Cl2: C, 53.66; H, 3.84; N, 6.95. Found: C, 53.36; H, 3.90; N, 6.81. M.S. (+FAB); 604 (M++1), 285, 241, 195, 173, 149, 91.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:51])[C:8]=2[N:17]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1

Procedure:
2-(2-Methoxyethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (4.7 g, 13 mmol) was treated with mCPBA (5.73 g, 24.9 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (4.23 g, 22.2 mmol) according to the method described in Part D of Example 8. The crude product was recrystallized twice from ethyl acetate to provide 0.233 g of 2-(2-methoxyethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as beige needles, mp 125-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:17])=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:6]2.[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:17])=[C:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:6]2[CH3:18]
Reactant: CI
Reactant: Cc1c(-c2ccccc2)[nH]c2cccc(Br)c12
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2cccc(Br)c12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 4-bromo-3-methyl-2-phenyl-1H-indole (1.574 g, 5.5 mmol) was reacted with k-t-butoxide (0.648 g, 5.775 mmol) and methyl iodide (0.820 g, 5.775 mmol) in DMF (15 ml) to give the product (1.188 g, 3.957 mmol, 72%) as a colorless oil. 1H DMSO-d6) δ 2.39 (s, 3H), 3.55 (s, 3H), 7.05 (t, J=7.8 Hz, 1H), 7.23 (dd, J=0.8, 7.6 Hz, 1H), 7.42-7.45 (m, 2H), 7.47-7.51 (m, 2H), 7.55 (t, J=6.9 Hz, 2H); [ESI(+)], m/z 300/302 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][S:10]([CH3:13])(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: CS(C)(=O)=O
Product: CS(=O)(=O)Cc1cc(Br)ccn1
Yield: 91 %

Procedure:
The title compound was prepared from 4-bromo-2-fluoro-pyridine and dimethylsulfone following a procedure analogous to that described in Step 1 for Intermediate 14. Yield: ca. 91% of theory (crude); LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:33]C(=O)OC(C)(C)C)[C:17]([NH:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[CH:21]=2)=[O:18])=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=1)[C:17]([NH:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=[O:18]
Reactant: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)n(C)n2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 100 flask was added tert-butyl (S)-3-(4-fluorophenyl)-1-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylcarbamate TFA 16.1.E (529 mg, 0.93 mmole), 20 ml of DCM, and 10 ml of TFA. The reaction was stirred at room temperature for 12 hours at which time the solvent was removed to give (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)propanamide diTFA 16.1F as a yellow solid (560 mg 100% yield). LCMS ESI (pos.) m/e: 354.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:53][CH3:54]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:53][CH3:54])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Yield: 47.8 %

Procedure:
A mixture of 0.0628 g (0.19 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0542 g (0.285 mmole) of toluenesulfonic acid monohydrate, 0.0527 g (0.19 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:1) and then recrystallization from acetonitrile to give 0.0519 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-255) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.[C:25]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>CCCCCC.C(NC(C)C)(C)C.C1(C)C=CC=CC=1.O>[OH:31][C:25]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:23]#[N:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Temperature: 0 °C
Yield: 79.1 %

Procedure:
Lithium diisopropylamide was made from 1.6M butyl lithium in hexane (325 ml), diisopropylamine (73 ml) and toluene (300 ml) under an inert atmosphere of nitrogen. A solution of p-methoxyphenylacetonitrile (76.5 g) in toluene (75 ml) was added to the solution under nitrogen over 15 minutes whilst the internal temperature was maintained below 10° C. After a half hour a solution of cyclohexanone (46 g) in toluene (50 ml) was added over 15 minutes to the reaction mixture under nitrogen whilst the internal temperature was maintained below 10° C. After a further half hour the mixture was blown over onto an ice-cold mixture of 12N hydrochloric acid (100 ml) and water (1l). The crystalline material was filtered off and then taken up into dichloromethane. The solution was washed with water and dried. The solvent was replaced with di-isopropyl ether by distillation. After cooling, the product was filtered and dried in vacuo to yield 91 g (79% yield ) of the title compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:23][N:24]=[C:25]=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CNC>ClCCl.O>[CH3:23][N:24]([CH3:25])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:13][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CC(=O)O)cc1
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution is prepared of 1.2 g (4.06 mmol) of 4-[2-(Boc-amino)ethoxy]benzeneacetic acid in 4 ml of dichloromethane and then 932 mg (4.87 mmol) of EDCI and 55 mg (0.406 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 400 mg (4.87 mmol) of dimethylamine hydrochloride are added. The reaction medium is then agitated at ambient temperature for 24 hours. The medium is then treated by the addition of 20 ml of water and then extracted 3 times with 50 ml of dichloromethane. The organic phases are then regrouped and washed 3 times with 50 ml of water, then dried on magnesium sulfate, and concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethanol mixture (95/5; v/v). In this way the expected product is obtained in the form of a colorless oil (yield=46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(CCN2CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
A mixture of 250 ml. butan-2-one, 15.47 g. (75 mmole) 1-(4-methoxybenzyl)-piperazine, 19.3 g. (75 mmole) ethyl 4-(2-bromoethyl)-benzoate and 20.7 g. (0.15 mole) powdered potassium carbonate is maintained at reflux temperature for 60 hours, then suction filtered while hot and the filtrate evaporated in a vacuum. After the addition of diethyl ether, the product crystallises, the yield being 17.5 g. (61% of theory) of the desired product; m.p. 75°-76° C. The hydrochloride is precipitated from the filtrate by means of hydrogen chloride-containing diethyl ether. After recrystallisation from aqueous ethanol, there are obtained 7.6 g. (23% of theory) of the desired product; m.p. 280°-281° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1>CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: N#CCc1cccc(N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
[3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile was prepared from (3-Amino-phenyl)-acetonitrile and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1223b. Title product was isolated as a beige solid (144 mg, 40%) after silica gel chromatography (ISCO 40 g 0-100% EtOAc in hexanes). 91% HPLC purity, MP=155-157, LCMS 279.11 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.45 (dd, J=7.8 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 3.82, s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[N:6][C:7]=1[Cl:8].F[B-](F)(F)F.[H+].N([O-])=O.[Na+].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>O.CCOC(C)=O>[C:20]([O:23][C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Br:1])[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(Cl)c(Br)c1
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-bromo-6-chloropyridin-3-amine (7.57 g, 36.5 mmol) in tetrafluoroboric acid (70 mL, 536 mmol, 48 wt. % solution in water) at 0° C. was added sodium nitrite (2.64 g, 38.3 mmol) in water (70 mL) slowly over 10 min. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered and washed with water. The resulting solid was dissolved in acetic anhydride (70 mL, 742 mmol) and stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give 5-bromo-6-chloropyridin-3-yl acetate. MS (ESI, pos. ion) m/z: 249.9 and 251.9 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH:27]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2]>CO.[Pd]>[NH:29]1[CH2:30][CH2:31][CH:27]([CH:4]([N:5]2[CH:9]=[C:8]([C:10]3[C:11]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:12]=4[N:13]=[CH:14][N:15]=3)[CH:7]=[N:6]2)[CH2:3][C:1]#[N:2])[CH2:28]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCN(C(=O)OCc5ccccc5)C4)c3)ncnc21
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl 3-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidine-1-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol (5 mL), and a catalytic amount of 5% Pd—C was added. The suspension was stirred at ambient temperature for 1 hour under an atmosphere of hydrogen provided by a balloon. A catalytic amount of 10% Pd—C was then added, and the reaction stirred for 2 hours under an atmosphere of hydrogen provided by a balloon. The mixture was then filtered, and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.15% NH4OH) to afford the product as a mixture of diastereomers (57 mg, 46%).