Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][S:50]([N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:44][CH:43]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][S:50]([N:53]6[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]6)(=[O:52])=[O:51])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(S(=O)(=O)CCc2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCS(=O)(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-[2-(4-bromo-phenyl)-ethanesulfonyl]-4-methyl-piperazine (94 mg) obtained in Step A in Example 1-D-296 instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-[5-(7-{4-[2-(4-methyl-piperazine-1-sulfonyl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-296) as a colorless solid (11 mg, 5%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([CH3:37])([CH3:36])[C:30]#[C:31]/[CH:32]=[CH:33]/[CH2:34]O>ClCCl>[Br:1][CH2:34][CH:33]=[CH:32][C:31]#[C:30][Si:29]([CH3:37])([CH3:36])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)C#C/C=C/CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
N-Bromosuccinimide (85.3 g, 0.48 mol) was added in portions to a nearly homogeneous solution of triphenylphosphine (128.2 g, 0.49 mol) and 2E-5-trimethylsilylpent-2-en-4-yn-1-ol (72.5 g, 0.47 mol) in dichloromethane (600 mL) under nitrogen and cooled in a dry ice/2-propanol bath to an initial temperature of below −20° C. The internal temperature of the reaction mixture was maintained at −10° C. to 0° C. throughout the addition by adjusting the rate of addition. The bath was allowed to warm to ambient temperature. After 2 hours, the reaction was complete. The reaction mixture was concentrated under vacuum to a thick paste and the residue was triturated with hexane (250 mL). The suspension was filtered and the solids and silica gel were rinsed with hexane (10×150 mL). The filtrate was concentrated under vacuum (30° C./60 mtorr) to obtain 44 g (89% yield) of 1-bromo-5-trimethylsilylpent-2-en-4-yne, a compound of formula (P), as a pale yellow oil: 1H-NMR (300 mHz, CDCl3) δ0.19 (s, 9H), 3.95 (d, 2H), 5.75 (d, 1H), 6.31 (dt, 1H) ppm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:13][NH:12][C:11]=1[NH2:20].[NH2:21][C:22]1NN=C(CCCCO)C=1C1SC2C=CC=CC=2N=1.CN.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:21][CH3:22])=[N:13][NH:12][C:11]=1[NH2:20]
Reactant: Nc1[nH]nc(CCCCO)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCCBr)c1-c1nc2ccccc2s1
Agent: CN
Solvent: C1CCOC1
Product: CNCCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (30 mg) was prepared using 185 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(4-bromobutyl)-2H-pyrazol-3-ylamine, which was derived from 4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-butan-1-ol, and 5 mL of a 2 M solution of methylamine in THF (10 mmol). MS (m/z, ES+): 302.4 (M+1, 100%).
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([SH:17])=[N:15][N:14]=[N:13]2)=[CH:8][CH:7]=1>O.O1CCCC1.[Cl-].[Na+].O>[CH3:3][S:17][C:16]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[N:13]=[N:14][N:15]=1
Reactant: CI
Reactant: Oc1ccc(-n2nnnc2S)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nnnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (2.06 g) in water (120 ml) followed by methyl iodide (3.5 ml) was added to a solution of 1-(4-hydroxyphenyl)-1H-tetrazole-5-thiol (10 g) in tetrahydrofuran (30 ml) and stirred at room temperature for 5 h. The mixture was poured into brine (120 ml), extracted with ethyl acetate (3×60 ml), dried (Na2 SO4) and evaporated to give the title compound as a brown solid (10.64 g). T.l.c. (Dichloromethane/methanol (990:10)), Rf=0.42
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[O:40][CH3:41]>N1C=CC=CC=1>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[O:8])=[C:12]([O:40][CH3:41])[CH:13]=3)[C:25]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc(C)on1
Reaction time: 5 h

Procedure:
5-Methyl-3-isoxazolecarbonyl chloride (20 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was purified by preparative HPLC (Hypersil BSD C18, 5 um, 100×21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partitioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore™ high performance extraction disk cartridge (C 18-SD octadecyl) to give cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide (14 mg, 38%). 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 2.53 (s, 3H), 2.76 (m, 3H), 3.37 (bm, 8H), 3.99 (s, 3H), 4.93 (m, 1H), 6.74 (s, 1H), 7.36 (m, 2H), 8.26 (m, 1H), 9.48 (s, 1H); LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ =546.4, Rt=1.82 min.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.CN([CH:21]=[O:22])C.P(Cl)(Cl)(Cl)=O>>[CH2:6]([CH:1]([N:8]1[C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:17])[CH3:7]
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(CC)n1c2ccccc2c2cc(C=O)c3ccccc3c21
Temperature: 130 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To 11H-benzo[a]carbazole (3.00 g, 9.12 mmol) in DMF (7.02 g, 96.1 mmol) is added phosphoryl chloride (14.0 g, 91.3 mmol) at 0° C. After stirring for 2 hours, the mixture is heated at 130° C., and it is stirred for 1 hour. The mixture is cooled at room temperature, and poured into ice-water. The crude product is extracted with CH2Cl2, and it is washed with water and brine. The organic layer is dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (1.43 g, 43%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.80-0.90 (m), 1.21-1.46 (m), 2.25 (m), 4.68 (m), 7.40 (t), 7.52-7.60 (m), 7.66-7.74 (m), 8.19 (s), 8.61 (d), 8.64 (s), 9.65 (d), 10.39 (s).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether was treated within 10 minutes with 9.7 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred for a further 1 hour. The mixture was then treated dropwise within 15 minutes at -10° C. with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 1 hour at 0° C. The reaction mixture was subsequently poured into 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 20 ml of ethyl acetate and the clear solution was diluted with 300 ml of petroleum ether and left to stand for 10 minutes at -20° C. The precipitated triphenylphosphine oxide was subsequently filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.32.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of intermediate 46, 2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) in dimethylformamide (4 mL) was stirred at 55-60° C. for 30 min after which the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic phase was washed with water, dried (Na2SO4), filtered and concentrated to provide 670 mg (Yield 87%) of the title compound as a yellow oil; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.78 (2H, s) 7.29-7.34 (1H, m) 7.59-7.64 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[NH2:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 102.9 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (5 mL) was added 1,1-dimethylethyl (2-aminoethyl)-methylcarbamate (0.09 mL, 0.5 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (61 mg, 100%). LC-MS (ES) m/z 659 (M+H)+; 1H-NMR (CDCl3) δ 1.39 (s, 9H), 1.70 (br, 1H), 2.32 (s, 3H), 2.65 (s, 2H), 2.82 (s, 2H), 3.22 (s, 3H), 3.60 (br, 1H), 6.34 (d, 1H), 7.03 (m, 4H), 7.34 (m, 1H), 7.48 (m, 2H), 7.64 (m, 1H), 7.84 (m, 2H), 8.14 (d, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33].[CH3:36][N:37](C)C=O>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>[C:36]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33])#[N:37]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (100 mg), dicyanozine (222 mg) and Pd(PPh3)4 (21.87 mg, 0.019 mmol) in N,N-dimethylformamide (4 ml) was heated at 180° C. for 400 seconds in a microwave reactor (CEM Discover) and then concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 50%-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>C(#N)C>[F:27][CH2:26][CH2:25][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1c(C2CCN(CCF)CC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-fluoroethane (0.01 ml). MS m/z (relative intensity, 70 eV) 291 (M+, 29), 259 (15), 258 (bp), 194 (22), 167 (11).
Reaction SMILES: Cl[C:2]([O:4]C)=[O:3].Br[C:7]1[CH:8]=[C:9]2[C:22]3[C:12]([CH2:13][C@@H:14]4[C@@H:19]([C:20]=3[CH:21]=1)[CH2:18][C@H:17]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:16][N:15]4[CH3:31])=[CH:11][N:10]2[Si](C(C)(C)C)(C)C>>[CH2:28]([N:25]([CH2:26][CH3:27])[C:24](=[O:30])[NH:23][C@H:17]1[CH2:18][C@H:19]2[C@@H:14]([CH2:13][C:12]3[C:22]4[C:9](=[CH:8][C:7]([C:2]([OH:4])=[O:3])=[CH:21][C:20]2=4)[NH:10][CH:11]=3)[N:15]([CH3:31])[CH2:16]1)[CH3:29]
Reactant: COC(=O)Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(=O)O)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With methyl chloroformate and 3-(13-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN2CCOCC2)CC1
Reaction time: 24 h
Yield: 29.6 %

Procedure:
To a solution of 1-Boc-4-(2-formyl-phenyl)-piperazine (500 mg, 1.7 mmol) in methanol (10 mL) was added morpholine (348 mg, 4.0 mmol) and sodium cyanoborohydride (315 mg, 5 mmol) and the mixture was stirred for about 24 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (10 ml), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography (1:1 hexanes/ethyl acetate) afforded the title compound as a colorless oil (182 mg, 30%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:19]2[CH2:18][C@H:17]3[N:20]([CH2:22][CH2:23][C@@:9]45[C@H:16]3[CH:15]=[CH:14][C@H:12]([OH:13])[C@@H:10]4[O:11][C:7]([C:8]=25)=[C:5]([OH:6])[CH:4]=1)[CH3:21].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].II>O.CO>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:6][C:5]2[CH:4]=[CH:3][C:19]3[CH2:18][C@H:17]4[N:20]([CH3:21])[CH2:22][CH2:23][C@:9]56[C:8]=3[C:7]=2[O:11][C@H:10]5[C@@H:12]([OH:13])[CH:14]=[CH:15][C@@H:16]46)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.5 g (37.5 mmol) of NaH (60% dispersion in mineral oil) was rinsed with 2×25 mL of hexanes to remove the oil. To the reaction mixture was added 140 mL of anhydrous DMF followed by 10.1 g (35 mmol) of morphine. This mixture was allowed to stir at room temperature for 30 minutes under nitrogen atmosphere, and 14.5 g (53 mmol) of N-(3-bromopropyl) phthalimide was added. The reaction mixture was allowed to stir 18 h at room temperature. The reaction was monitored by thin layer chromatography (silica, 7:2:1:1, MeOH:EtAc:NH40H:H2O, I2 visualization), which showed that the reaction was incomplete. To the reaction mixture 0.15 g (3.75 mmol) of NaH (60% in oil) was added, and the mixture was allowed to stir for an additional 1.5 h. The mixture was poured into 350 mL of ice-water and extracted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2×250 mL of ethyl acetate. The organic layers were combined and washed with 2×150 mL of water, 150 mL of 1N NaOH and 2×150 mL of water. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized with diethyl ether to give 12.9 g (27.3 mmol, 77%) of the desired product 13 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=O)=[CH:12][S:13][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl.[OH:31][CH2:32][C:33]1([OH:37])[CH2:36][NH:35][CH2:34]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([N:35]2[CH2:36][C:33]([CH2:32][OH:31])([OH:37])[CH2:34]2)=[O:17])=[CH:12][S:13][CH:14]=1
Reactant: O=C(O)c1cscc1Nc1ccc(I)cc1F
Reactant: OCC1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1cscc1Nc1ccc(I)cc1F)N1CC(O)(CO)C1
Reaction time: 0.08 h
Yield: 106.8 %

Procedure:
4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (200 mg, 0.551 mmol), 4-(dimethylamino)pyridine (202 mg, 1.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg, 0.662 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(hydroxymethyl)azetidin-3-ol hydrochloride (72 mg, 0.516 mmol) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 20% citric acid. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with 5% lithium chloride, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from dichloromethane to afford 1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol, quantitative yield) as off-white crystals: MS (EI) for C15H14FIN2O3S: 449 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[C:34]([O:33][C:31](=[O:32])[CH2:30][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(Sc2ccc(O)c(C)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 100 mL round-bottomed flask was charged with bis-(4-hydroxy-3-methylphenyl)-sulfide (8.6 g, 34.9 mmol), finely powdered Cs2CO3 (11.9 g, 36.7 mmol), and anhydrous DMF (35 mL). Next, tert-butyl bromoacetate (5.2 mL, 34.9 mmol, Aldrich) was added dropwise, and the reaction was stirred vigorously overnight at room temperature. The reaction was poured into 500 mL of water and extracted with 3×50 mL of methylene chloride. The combined organics were washed with 2×150 mL of water, dried over Na2SO4, and concentrated to a slightly yellow oil. The mixture was then purified by flash chromatography (SiO2 gel 60, eluted with 10% hexanes in DCM-5% hexanes in DCM-100% DCM). The fractions containing only desired product 1.1 were combined and concentrated to a white solid (3.5 g). The mixed fractions were combined, concentrated, and resubjected to the same chromatography conditions to yield an additional 2.0 g of pure 1.1. 1H NMR (400 MHz) (CDCl3) δ 7.13 (2H, m); 7.06 (2H, m); 6.70 (1H, d, J=8.3 Hz); 6.59 (1H, d, J=8.4 Hz); 4.50 (2H, s); 2.23 (3H, s); 2.20 (3H, s); 1.48 (9H, s).
Reaction SMILES: N1[C:6]2[CH:7]=[CH:8]S[C:5]=2[C:4](=O)NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)[CH2:22][CH2:23][O:24][CH2:25][Cl:26]>>[CH2:23]([O:24][CH2:25][Cl:26])[C:22]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using thieno[3,2-d]pyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 87%) as a pale yellow powder.