Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[CH3:10][C:11]1([CH2:17][NH2:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CN1C(=O)CCC1.CCOC(C)=O.[Cl-].[Na+].O.O>[F:8][C:7]1[C:2]([NH:18][CH2:17][C:11]2([CH3:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: CC1(CN)CCOCC1
Reactant: Fc1ccc(F)c(F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(CNc2nc(F)ccc2F)CCOCC1
Temperature: 70 °C

Procedure:
A mixture of 2,3,6-trifluoropyridine (858 mg, 6.45 mmol), (4-methyltetrahydro-2H-pyran-4-yl)methanamine (1000 mg, 7.74 mmol) and triethylamine (2.158 mL, 15.48 mmol) in NMP (16 mL) was heated at 70° C. for 1 hr. The reaction mixture was allowed to ambient temperature and was diluted with EtOAc (˜100 mL), brine (˜50 mL) and water (˜50 mL). The separated organic layer was washed with brine (1×), 0.3N aqueous HCl (2×), saturated aqueous NaHCO3 solution (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo to provide crude 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a colorless oil, which was directly used in the next reaction without further purification. Yield: 1.4 g. LCMS (m/z): 243.1 [M+H]+; Retention time=0.86 min.
Reaction SMILES: [CH:1]1([NH:4][S:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)OCC>[CH:1]1([N:4]2[S:5](=[O:7])(=[O:6])[N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:18][CH2:17]2)[CH2:2][CH2:3]1
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)S1(=O)=O
Reaction time: 15 h

Procedure:
410 mg of tert-butyl cyclopropylsulfamoylcarbamate, 150 μl of 1,2-dibromoethane and 719 mg of K2CO3 were boiled under reflux in 6 ml of anhydrous acetone for 9 hours. The reaction mixture was left to stand at RT for 15 hours. Then 20 mg of tetrabutylammonium iodide were added, and the mixture was boiled under reflux for 9 hours. It was then diluted with 100 ml of EA and washed twice with 10 ml of water each time. After drying over Na2SO4, the solvent was removed in vacuo. 400 mg of a colorless oil were obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][NH2:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(C#N)CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CN)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
To a stirred solution of 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (3.5 g, 11 mmol) in THF (35 ml) at 0° C. was added dropwise lithium aluminium hydride (1M solution in ether, 44 ml, 44 mmol). The reaction was allowed to warm up to room temperature and stirred for 4 hours until complete. The reaction mixture was cooled to 0° C., water (1.66 mL) was added followed by NaOH (2.0M, 1.66 mL) and water (4.97 mL). The mixture was filtered through a short pad of celite, eluting with dichloromethane:methanol (97:3, 150 ml) and concentrated in vacuo. Solid obtained was partitioned between ethyl acetate (50 ml) and sodium bicarbonate (50 ml). The organic layer was then dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (2.04 g, 58%). LRMS APCI+ m/z 322 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:26][CH2:25][C:22]([C:27]([OH:29])=[O:28])([CH2:23][CH2:24]4)[CH2:21][CH2:20]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][CH:3]=1.[OH-].[Na+].[I:37]I>O.C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:20][CH2:21][C:22]([C:27]([OH:29])=[O:28])([CH2:25][CH2:26]4)[CH2:23][CH2:24]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][C:3]=1[I:37]
Reactant: II
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)c(I)c2)c1=O
Yield: 18.9 %

Procedure:
To a solution of 50 mg 4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylic acid (Example 27a) (0.107 mmol) in water (10 ml) containing 1 eq. of 1N NaOH (110 μL) was added at rt a solution of 30 mg of iodine (0.107 mmol) in ethanol (1 ml). The reaction mixture was concentrated in vacuo and the crude product purified by preparative chromatography to afford 12 mg (20%) of desired product (MH+=592.89).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39](=O)[CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:39][CH3:40])[C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of tert-butyl 3-(3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (0.90 g, 1.69 mmol) and acetaldehyde (0.22 g, 5.06 mmol) in dichloroethane (10 mL), was added acetic acid (0.61 g, 10 mmol) and the reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (1.07 g, 5.05 mmol) was added at 0° C. and the reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure giving the title compound which was used without further purification (0.85 g).
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[CH2:26]([C@H:33]([C@@H:49]([O:53][Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])[C@@H:50]([OH:52])[CH3:51])[CH2:34][O:35][CH2:36][C@@H:37]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:38](O)=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:26]([C@@H:33]1[C@@H:49]([O:53][Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:56])[CH3:57])[C@H:50]([CH3:51])[O:52][C:38](=[O:39])[C@@H:37]([NH:41][C:42](=[O:43])[O:44][C:45]([CH3:47])([CH3:48])[CH3:46])[CH2:36][O:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)[Si](O[C@H]([C@H](COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)Cc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of DMAP (442 mg, 3.62 mmol, 6.00 equiv) and 2-methyl-6-nitrobenzoic anhydride (415 mg, 1.21 mmol, 2.00 equiv) in CH2Cl2 (92 mL, 6.5 mM) was added a solution of (R)-3-((2S,3R,4S)-2-benzyl-4-hydroxy-3-(triisopropylsilyloxy)pentyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (334 mg, 0.603 mmol, 1.00 equiv) in CH2Cl2 (15 mL) via a syringe pump over 8 h. The resulting solution was stirred at room temperature for an additional 8 h, concentrated, and purified by automated silica gel column chromatography (0-20% hexanes in acetone) to provide tert-butyl (3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(triisopropylsilyloxy)-1,5-dioxonan-3-ylcarbamate (318 mg, 98%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.34-7.07 (m, 5H), 5.30-5.14 (m, 1H), 5.11 (d, J=8.1 Hz, 1H), 4.53 (q, J=8.3 Hz, 1H), 4.08 (dd, J=11.6, 6.9 Hz, 1H), 3.88 (dd, J=6.3, 5.0 Hz, 1H), 3.60 (dd, J=11.7, 5.9 Hz, 1H), 3.44 (d, J=11.6 Hz, 1H), 3.07 (t, J=10.3 Hz, 1H), 2.92 (dd, J=13.3, 4.0 Hz, 1H), 2.76 (t, J=12.4 Hz, 1H), 1.99 (td, J=10.6, 5.0 Hz, 1H), 1.50-1.38 (m, 12H), 1.14-0.99 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 171.75, 154.92, 140.37, 129.13, 128.35, 126.01, 79.99, 78.88, 73.17, 70.69, 52.89, 49.64, 34.63, 28.28, 19.51, 18.24, 18.19, 13.14; HRMS-ESI (m/z) [M+H]+ calc'd for C29H49NO6SiNa, 558.3221. found, 558.3224.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22]>>[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH:22][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Reactant: CCC(C)CN
Product: CCC(C)CNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1

Procedure:
Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and racemic 2-methylbutylamine [96-15-1] (42 mg, 0.5 mmol). Purification by preparative RP-HPLC provided 1-{5-[6-(2-methyl-butylamino)-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-ethanone as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-1.01 (m, 5H) 1.19-1.30 (m, 1H) 1.50-1.61 (m, 4H) 1.89 (dq, J=13.29, 6.74 Hz, 1H) 2.54 (s, 2H) 3.26-3.33 (m, 1H) 3.40-3.49 (m, 1H) 4.57 (t, J=5.73 Hz, 1H) 6.43-6.47 (m, 1H) 7.21 (s, 1H) 7.56-7.58 (m, 1H) 7.61-7.67 (m, 2H) 7.90 (s, 1H). LRMS (ESI) m/z 329.1 [(M+H)]+, calc'd for C17H20N40S: 328.44.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:12])[CH:6]2[CH3:13])#[N:2].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:14][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[S:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1C(=S)Nc2ccc(C#N)cc21
Solvent: ClCCl
Product: CC1(Cl)C(=S)Nc2ccc(C#N)cc21

Procedure:
A solution of 5-cyano-3-methylthiooxindole (950 mg, 4.66 mmol) and N-chlorosuccinimide (800 mg, 5.95 mmol) in 100 ml of methylene chloride was stirred at room temperature for 24 hours. The solvent was removed in vacuo, yielding 3-chloro-5-cyano-3-methylthiooxindole and the residue, which was dissolved in a minimum of tetrahydrofuran, was added to a vigorously stirred slurry of red mercuric oxide (1.00 g, 4.7 mmol) and boron trifluoride ethereate (670 mg, 4.7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After 2 hours, the reaction mixture was filtered through a pad of Celite. The pad was washed with three 100-ml portions of chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform-ethanol (9:1 v/v) gave 5-cyanoisatin as an orange solid (525 mg, 65%), mp 270°-272° (dec); ir (KBr) 3100 (NH), 2220 (C≡N), 1730 (C=O) and 1710 cm-1 (C=O); nmr (DMSO-d6)π-1.30 (1H, b, s, NH), 2.00 (d of d, 1H, J4,6 =2 Hz, J6,7 =8.5 Hz, H6), 2.10 (d, 1H, J4,6 =2 Hz, H4), and 2.90 (d, 1H, J6,7 =8.5 Hz, H7); mass spectrum, m/e obs. 172.0238 (calc. 172.0272).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C.[Na+].[I-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaI (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7](O[Si](C)(C)C)=[C:6](O[Si](C)(C)C)[CH2:5][CH2:4]1)[CH3:2].[ClH:20].Cl.[C:22]([CH:25]([NH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[NH:24])[NH2:23]>>[ClH:20].[ClH:20].[NH2:24][C:22]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:31][C:7]2[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=2[N:23]=1
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)C(N)C(=N)N
Agent: Cl
Product: CCOC(=O)c1nc2c(nc1N)CCN(CC)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)azepine and ethyl 2-amidino-2-aminoacetate dihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][C:19]1(N)[CH2:24][CH2:23][N:22]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:21][CH2:20]1>CC(O)C.CO>[C:27]1([CH:25]([N:22]2[CH2:23][CH2:24][C:19]3([NH:16]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:18]3)[CH2:20][CH2:21]2)[CH3:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(c1ccccc1)N1CCC(N)(CN)CC1
Solvent: CO
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CCC2(CC1)CN/C(=N\C(=O)c1nc(Cl)c(N)nc1N)N2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (1.7 g, 4.54 mmol) and 4-aminomethyl-1-(1-phenyl-ethyl)-piperidin-4-ylamine (Intermediate BM) (1.6 g, 4.59 mmol) in propan-2-ol (50 ml) is stirred at 80° C. for 16 hours. The reaction mixture is concentrated in vacuo and purified by column chromatography (basic alumina, 0-2% MeOH in DCM) to obtain pale yellow solid. The compound obtained is further dissolved in MeOH and precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford the title compound as off-white solid; [M+H]+ 429
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]([CH3:37])=[C:35](B(O)O)[C:34]([CH3:41])=[N:33]1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:35]2[C:34]([CH3:41])=[N:33][N:32]([CH3:31])[C:36]=2[CH3:37])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Reactant: Cc1nn(C)c(C)c1B(O)O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3c(C)nn(C)c3C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 192, starting from tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid, pinacol ester, the title compound was obtained as a black sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31]Br>ClCCl.C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCCBr
Reactant: c1ncc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (5-{4-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenoxy]-phenyl}-oxazole (150 mg, 0.4 mmol) in anhydrous dichloromethane (0.5 mL) was added methyl-4-bromobutyrate (80 mg, 0.44 mmol) in dichloromethane (0.5 mL) and triethylamine (81 mg, 0.8 mmol. The resulting mixture was purged with nitrogen and stirred at rt for 16 h. dichloromethane was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with brine, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (40% EtOAc/Hexane) to obtain the title product as yellow oil (95 mg, 55%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].P(C1C=CC=CC=1)(C1C=CC=CC=1)[C:13]1[CH:18]=CC=C[CH:14]=1.CC(C(OC1C=CC(C(O)CNC)=CC=1OC(C(C)(C)C)=O)=O)(C)C.Cl>CN(C)C=O.C(N(CC)CC)C.Cl[Pd]Cl.[Cu]I>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])#[C:13][CH3:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CNCC(O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1ccccc1S(N)(=O)=O
Yield: 80 %

Procedure:
To a solution of 28.3 g (0.1 mole) of 2-iodophenylsulfonamide in 350 ml of dimethylformamide and 100 ml of triethylamine are added 1.0 g of palladium dichloro-bis(triphenylphosphite) complex, PdCl2 [P(C6H5)3 ]2, and 0.5 g of copper (I) iodide (CuI). Gaseous propine is then introduced into this solution until the starting material is completely reacted. The reaction mixture is filtered and the residue is concentrated in vacuo and then taken up in water. The precipitate is isolated and dried. Recrystallisation from ethyl acetate/hexane yields 15.6 g (80%) of 2-(propyn-1-yl)phenylsulfonamide with a melting point of 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28](=[O:29])[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]([CH2:10][CH3:11])[C:5]2=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(Nc1ccc(OC)cc1)c1cnc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC1c2cnc(Cl)nc2N(c2ccccc2)C(=O)N1c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
To a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-propyl]-(4-methoxy-phenyl)-amine (0.19 g; 0.59 mmol) (from Example 7c supra) in toluene (2 mL) was added phenyl isocyanate (83 μL; 0.76 mmol) (Aldrich). The solution was heated in an oil bath at 110° C. for 1 hour. Upon cooling to room temperature, the reaction was concentrated. The residue was triturated with hexanes and then dried briefly under high vacuum. The solid residue (intermediate urea) was dissolved in freshly distilled tetrahydrofuran (2 mL), cooled to −3° C. and treated with potassium tert-butoxide (1.0 M in tetrahydrofuran; 0.65 mL; 0.65 mmol) (Aldrich). After 15 minutes in the cold, the reaction mixture was filtered through a silica gel pad (1 g) and washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography (Biotage, 40S, 20:80 to 40:60 ethyl acetate-hexanes gradient) to give (±)-7-chloro-4-ethyl-3-(4-methoxy-phenyl)-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a solid. (Yield 0.14 g; 60.2%). The NMR of this material showed only two singlets for the pyrimidine proton indicating a mixture of the desired product and the corresponding 7-bromo compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 63.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) and commercially available cyclohexanecarboxylic acid (46 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (84 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 45 mg of the title compound (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated at reflux overnight with a homogeneous solution obtained after several minutes of heating. After cooling, the methanol was removed in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 10.2 g of title compound as a brown solid, m.p. 41–43° C.