Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Cl.Cl.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=[O:32]>ClCCl>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:31]([NH:30][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Agent: Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (934.9 mg, 2.6 mmol) and Hunig's base [7087-68-5] (1.8 mL, 10.6 mmol) in dichloromethane (26 mL) was added 2-isocyanato-2-methylpropane [1609-86-5] (340 μL, 2.9 mmol). The suspension was permitted to stir and warm to ambient temperature over 17 h and was then partitioned between brine and ethyl acetate. The organic phase was reduced in volume to precipitate product as 442.1 mg of yellow solid. A 129.3 mg aliquot was purified by preparative RP-HPLC to yield 61.8 mg of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N-(tert-butyl)piperazine-1-carboxamide as a white powder, mp. 199-200° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 8H) 2.51 (s, 1H) 3.30 (s, 1H) 3.39-3.46 (m, 4H) 3.48-3.54 (m, 4H) 7.26 (d, J=10.11 Hz, 1H) 7.61 (s, 1H) 7.88 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.15, 43.05, 45.27, 49.94, 99.27, 110.77, 126.00, 131.50, 136.54, 155.16, 156.93. LRMS (ESI) m/z 381.1/383.1 [(M+H)]+, calc'd for C15H21BrN6O: 381.28.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH:38]=O)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH2:38][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4cc(C)c(C=O)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C1COCCN1
Product: COc1cc(-c2csc3c(-c4cc(C)c(CN5CCOCC5)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-{4-[4-amino-7-(5-formyl-4-methylthien-2-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (70.0 mg, 0.127 mmol) and morpholine (44.2 μL, 0.507 mmol) were reacted according to General Procedure B followed by HPLC purification to give the title compound as a light yellow powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions a): MH−=622, RT=4.73 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (dd, J=8.4, 0.80 Hz, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20 (s, 1H), 7.12–7.16 (m, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 5.69 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.63 (s, 2H), 3.60 (t, J=4.6 Hz, 4H), 2.46 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 343.1 and 345.1 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][N:35]1[C:39]([CH3:40])=[CH:38][C:37]([C:41](Cl)=[O:42])=[N:36]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:37]3[CH:38]=[C:39]([CH3:40])[N:35]([CH3:34])[N:36]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: Cc1cc(C(=O)Cl)nn1C
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (40 mL). After stirring for 10 minutes, 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride (0.4 g, 2.6 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (80 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.3 g, 38%) as a white solid: mp 213-215° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.28 (s, 3H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.79 (s, 3H), 4.86 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.1 and 12.4 Hz, 1H), 6.44 (s, 1H), 7.65-7.79 (m, 3H), 8.69 (t. J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 10.66, 21.97, 30.93, 36.39, 37.80, 48.86, 105.53, 121.71, 127.01, 131.51, 132.78, 134.70, 139.60, 140.35, 144.26, 161.91, 167.00, 167.56, 169.83, 172.75; Anal. calcd. for C20H19N5O5+0.4H2O: C, 57.66; H, 4.79; N, 16.81. Found: C, 57.85; H, 4.80; N, 16.64.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:19]([C:21]([F:24])([F:23])[F:22])=[N:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-(4-morpholinyl)benzoate (4.0 g) in CF3COOH (20 mL) was heated at reflux temperature for 8 h. When TLC analysis indicated consumption of starting material, the mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was diluted with aqueous NaHCO3 and extracted with EtOAc (250 mL×3).The combined organic layers were washed with brine (250 mL×2), dried over anhydrous Na2SO4. After filtration, the solvent was removed by rotary evaporator. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:4 to afford the desired product as a pale solid. (4.3 g, 82.7%). 1H NMR (300 MHz, DMSO-d6): δ ppm 13.47 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 3.96 (s, 3H), 3.79 (t, 4H, J=4.5 Hz), 3.17 (s, 4H). LC-MS: m/e=330.1 [M+1]+.
Reaction SMILES: [B:1].[CH2:2](O)[CH2:3][CH:4]([CH3:6])[CH3:5]>>[CH2:2]([B:1]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [B]
Reactant: CC(C)CCO
Product: CC(C)CCB(CCC(C)C)CCC(C)C

Procedure:
An intended product having a boron content of 4.3% by weight (calculated: 4.50%) and a purity of 95.5% was obtained from 226 parts by weight of triisoamyl boron and 88 parts by weight of isoamyl alcohol in the same manner as in Referential Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.ClC[CH2:22][N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]1.BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:27][CH2:28][N:23]1[CH2:22][CH2:26][CH2:25][CH2:24]1)[CH:10]=3
Reactant: ClCCN1C=CC=CC1
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCN3CCCC3)cc1O2

Procedure:
2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10, using 1-(2-chloroethyl)pyridine in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (100 mg, 46% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:15][N:14]=1>C(OC(C)C)(C)C>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: CCCCSc1nc(O)ns1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCCCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
0.5 ml of triethylamine and 4.78 g of methyl isocyanate were added to a solution of 95 g of 3-hydroxy-5-n-butylthio-1,2,4-thiadiazole in 50 ml of isopropyl ether and the mixture was stirred for 2 hours at 20° C and was vacuum filtered. The recovered precipitate was washed with isopropyl ether and dried to obtain 11.2 g of 2-(N-methylcarbamoyl)-5-n-butylthio-1,2,4-thiadiazole-3-one melting at 102° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6](OC)[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc(OC)cc1=O
Product: CCn1ncc(Cl)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=159.1, 161.1 (M+H+), was prepared in accordance with the general method of example 23c by treatment of 2-ethyl-5-methoxy-2H-pyridazin-3-one with phosphorus oxychloride.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)C.[CH:22]1(N)C2C(=CC=CC=2)CCC1.ClC1C(C)=NC=C(C)N=1>>[CH3:1][C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:22]2)=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1
Reactant: NC1CCCc2ccccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: Cc1cnc(C)c(Cl)n1
Product: Cc1cnc(C)c(NC2CCCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1,2,3,4-tetrahydronaphthalen-1-amine and 3-chloro-2,5-dimethylpyrazine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.91, 2.11, 2.31, 2.40, 2.87, 4.50, 5.16, 7.21, 7.35, 7.62; MS (ESI+) for C16H19N3 m/z 254.4 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>C(Cl)Cl>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][S:41]([C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)(=[O:43])=[O:42])=[CH:16][CH:15]=1
Reactant: COc1ccc2nccc(-c3ccc(CCN)cc3)c2n1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)cc3)c2n1
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a stirred solution of 2-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)phenyl]ethylamine hydrochloride salt (0.10 g, 0.26 mmole), from Example 1a, in dry CH2Cl2 (25 mL) at RT was added triethylamine (0.11 mL, 0.78 mmole) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride (69 mg, 0.26 mmole). After 24 h, the reaction contents were concentrated. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.10 g, 75%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.06 (d, J=4.5 Hz, 1H), 8.57 (d, J=9.0 Hz, 1H), 8.26 (d, J=4.6 Hz, 1H), 8.10 (d, J=9.1 Hz, 2H), 7.73 (m, 3H), 7.45 (d, J=9.0, 1H), 7.17 (m, 2H), 4.25 (s, 2H), 4.06 (s, 3H), 3.77 (m, 2H), 3.31 (m, 2H). LC-MS (ES) m/e 507 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[F:1])[CH:9]=1)=[O:27]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(F)cnn1C
Yield: 58 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 21 mg (58% yield) of Compound 37: LCMS m/z (%)=377 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.06 (ddd, J1=11.4 Hz, J2=8.6 Hz, J3=2.8 Hz, 1H), 6.99 (dd, J1=9.6 Hz, J2=9.6 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −119.93 (m, 1F), −127.63 (m, 1F) −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[C:14]([NH2:15])=[C:13]([O:16][CH3:17])[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:17][O:16][C:13]1[C:14]2[N:15]=[C:2]([NH2:1])[N:4]3[CH2:8][CH2:7][N:6]=[C:5]3[C:9]=2[CH:10]=[CH:11][C:12]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COc1c(OCCCN2CCOCC2)ccc(C2=NCCN2)c1N
Reactant: N#CBr
Solvent: ClCCl
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 mL) precooled to 0° C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT=0.17 min, MH+=360.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[F:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[N:25]([CH3:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27].[H-].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:24][C:22]1[CH:21]=[CH:20][C:19]([N:25]([CH3:36])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[C:18]([F:17])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C(N)=O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
6-Carbamoyl-4-chloro-7-methoxyquinoline (41 mg, 0.1744 mmol) and N-(2-fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea (57 mg, 0.2048 mmol) were dissolved in dimethylsulfoxide (1.0 ml), and then sodium hydride (8.4 mg, 0.2093 mmol) was added and the mixture was heated and stirred at 85° C. for 30 minutes. After cooling the reaction solution to room temperature, water was added and the precipitated crystals were filtered out. The crystals were then suspended in acetone: diethyl ether=1:2 and refiltered out, washed with diethyl ether and dried by aspiration to obtain the title compound (46 mg, 0.0961 mmol, 55.13%) as yellow crystals.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:6][C:7]([C:10]2[S:11][C:12]([C:16](=[O:18])[CH3:17])=[C:13]([CH3:15])[N:14]=2)=[N:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[C:5]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:6][C:7]([C:10]2[S:11][C:12]([CH:16]([OH:18])[CH3:17])=[C:13]([CH3:15])[N:14]=2)=[N:8][CH:9]=1
Reactant: CC(=O)c1sc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)sc1C(C)O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
NaBH4 (46 mg, 1.2 mmol, 3.0 equiv.) was added to a solution of 1-(2-(5-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanone (Compound 297 (150 mg, 0.4 mmol, 1.0 equiv.) in THF (2 mL) and methanol (2 mL) at rt. The mixture was stirred for 0.5 h, then, concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was recrystallized with methanol and isopropyl ether to afford 1-(2-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanol (Compound 296) (120 mg, 80%). LC-MS (m/z)=377.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.70-0.78 (m, 2H), 0.95-1.03 (m, 2H), 1.41 (d, J=5.2 Hz, 3H), 1.89-1.96 (m, 1H), 2.38 (s, 3H), 5.04-5.08 (m, 1H), 5.75 (d, J=2.8 Hz, 1H), 6.62 (s, 1H), 8.47 (s, 1H), 9.51 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[CH2:7][CH3:8].[I:17]I.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH2:6]([C:9]1[CH:10]=[C:11]([F:16])[C:12]([I:17])=[C:13]([F:15])[CH:14]=1)[CH2:7][CH3:8]
Reactant: II
Reactant: CCCc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1cc(F)c(I)c(F)c1
Temperature: 25 °C

Procedure:
22 ml of a 1.6N butyllithium solution in hexane were added dropwise during 30 min. to a solution of 5 g of 1-propyl-3,5-difluorobenzene in 50 ml of dry tetrahydrofuran at -70° C. and left to react at -70° C. for 1 hour. Then, a solution of 8.95 g of iodine in 20 ml of dry tetrahydrofuran was added dropwise at -60° within 10 minutes and the mixture was gradually warmed to room temperature within a further 30 minutes. The resulting yellow solution was then treated with 40 ml of a 10 percent aqueous sodium bicarbonate solution and extracted with ether. The ether solution was washed with saturated sodium chloride solution and several times with water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue over 200 g of silica gel with hexane gave 1-propyl-3,5-difluoro-4-iodobenzene as a colourless liquid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:9]([N+]1C2C=CC=CC=2[Te]C=1C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:26][O:27][C:28]1[C:29]([O:38][CH3:39])=[CH:30][C:31]2[Te:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:9]([N+:33]1[C:32]2[CH:37]=[C:28]([O:27][CH3:26])[C:29]([O:38][CH3:39])=[CH:30][C:31]=2[Te:35][C:34]=1[CH3:36])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nc(C)[te]c2cc1OC
Reactant: Cc1[te]c2ccccc2[n+]1Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: COc1cc2[te]c(C)[n+](Cc3ccccc3)c2cc1OC

Procedure:
This compound was prepared in the same way and on the same scale as the compound of Example 52, except that 5,6-dimethoxy-2-methylbenzotellurazole (Example 19) was used in place of 2-methylbenzotellurazole. Yield 0.50 g of a pale gray powder, m.p. 179°-182° C. (dec). The infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for a mixture of desired compound and the hydro salt 5,6-dimethoxy-2-methylbenzotellurazole.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([O:14]CC)=[O:13])[C:3]([F:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH3:31]O.O>O1CCCC1>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([OH:14])=[O:13])[C:3]([F:6])([CH2:4][CH3:31])[CH3:5]
Reactant: CO
Reactant: CCOC(=O)C(Cc1cccc(C(F)C(C)(C)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(F)C(F)c1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (2.849 g, 7.223 mmol), sodium hydroxide (0.58 g, 14.4 mmol), methanol (10 ml), water (10 ml) and tetrahydrofuran (10 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-2-[3-(1,2-difluoro-2-ethylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid as a liquid.
Reaction SMILES: [CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Reactant: O[C@@H]1CNCC[C@]1(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@]1(O)Cc1ccccc1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of 5.0 g (24 mmol) (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine in 150 ml DMF were added 7.4 g (24 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 5.0 g (36 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 72 hours. After the addition of water the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 10.5 g (24 mmol, 100%) (3R,4R)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.