Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a DCM 200 mL solution of 2,4,6-trifluorobenzoic acid (20 g, 0.11 mol) and DMF (0.5 mL, 6.46 mmol) was added oxalyl chloride (21.6 g, 0.17 mol) dropwise. The reaction mixture was stirred at room temperature for 1 hr and the solvent was removed under reduced pressure to give the title compound as crude product (22 g).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9]([Cl:24])=[O:10])[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CSC2(C(=O)O)CCN(OC)CC2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(CSC2(C(=O)Cl)CCN(OC)CC2)cc1
Temperature: 100 °C

Procedure:
700 mg 1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carboxylic acid (from Step 5) was dissolved in 10 ml toluene, 1 drop N,N-dimethylformamide was added, followed by 400 mg thionyl chloride. The mixture was heated to 100° C. for 1 hour, at which time the evolution of gas has ceased. The solvent was evaporated, to yield crude 1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carbonyl chloride.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[CH3:18][N:19]=[C:20]=[O:21]>CO>[CH3:18][NH:19][C:20](=[O:21])[NH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: CN=C=O
Reactant: Cc1cn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CO
Product: CNC(=O)N[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 1 h

Procedure:
To a solution of 7 (0.48 g, 2.00 mmol) in 15 ml of methanol, methyl isocyanate (0.13 g, 2.20 mmol) was added slowly. The solution was stirred at 0° for 1 h, during which period, white crystals precipitated out. The product was collected by filtration, washed with cooled methanol, and dried, to give 0.54 g (90%). The compound softened at 114° and effervesced at 120°; TLC: Rf 0.38. Anal. (C12H18N4O5) C, H, N.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8].C(OC(=O)C)(=O)C>>[C:2]([C:3](=[CH:10][O:9][CH2:7][CH3:8])[C:4]#[N:5])(=[O:1])[CH3:6]
Reactant: CC(=O)CC#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(C)=O
Temperature: 25 °C

Procedure:
3-Oxo-butyronitrile (4.94 g, 60.9 mmol), triethylorthoformate (15.0 mL, 90.2 mmol), and acetic anhydride (0.3 mL, 2.7 mmol) were warmed to about 95-115° C. for about 1 hours, over which time a distillate was collected and discarded. After cooling the resultant mixture to room temperature, hexanes were added and a precipitate formed. The resultant mixture was filtered and the solids washed with hexanes, to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:30][CH2:29][C:14]3([C:19]4=[CH:20][CH:21]=[CH:22][N:18]4[C:17]4[CH:23]=[CH:24][C:25]([CH2:27][OH:28])=[CH:26][C:16]=4[O:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:12][CH2:13][C:14]3([O:15][C:16]4[CH:26]=[C:25]([CH:27]=[O:28])[CH:24]=[CH:23][C:17]=4[N:18]4[CH:22]=[CH:21][CH:20]=[C:19]34)[CH2:29][CH2:30]2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C=O)ccc2-n2cccc23)cc1OC

Procedure:
A solution of (4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (270 mg, 0.62 mmol) and manganese dioxide (270 mg, 3.1 mmol) in dichloromethane (5 mL) was stirred at 60° C. overnight. The reaction was filtered, evaporated and submitted to the next step without further purification. ESI-MS m/z calc. 430.5, found 431.7 (M+1)+; Retention time: 2.01 minutes (3 min run).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[Mg]Br>C1COCC1>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: Br[Mg]c1cccs1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)sc2c1
Yield: 72.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.97 g, 4.5 mmol) in THF (15 mL) was reacted with a 0.60M THF solution of 2-thienylmagnesium bromide (31.8 mL, 13.5 mmol) (prepared from 2-bromothiophene, n-butyllithium, and magnesium bromide in ether) at ambient temperature. Purification by chromatography (silica gel, 1:1 hexane:ethyl acetate, 10% methanol, 0.1% ammonium hydroxide) gave 1.55 g (72%) of the title compound as a yellow foam: 1H NMR (300 MHz) δ1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.42 (m, 4H), 2.66 (t, J=5.8 Hz, 2H), 3.88 (s, 3H), 4.12 (t, J=5.9 Hz, 2H), 6.96 (m, 4H), 7.16 (d, J=2.5 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ24.1, 25.9, 55.1, 55.6, 57.7, 66.3, 104.4, 114.4, 115.0, 124.2, 127.1, 127.7, 127.7, 130.3, 131.5, 132.3, 133.6, 134.2, 135.0, 140.0, 158.0, 163.4, 192.8; IR (CHCl3) 1649, 1599 cm-1 ; MS (FD+) m/e 477 (M+); Anal. calc'd. for C27H27NO3S2 : C, 67.89; H, 5.70; N, 2.93. Found: C, 68.13; H, 5.89; N, 2.78.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[C:35]([NH:38][CH2:39][CH2:40][CH2:41][N:42]5[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]5)[N:34]=[CH:33][N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)n(-c2ccc(F)cc2)n1
Reactant: CN1CCN(CCCN)CC1
Solvent: CCO
Product: CN1CCN(CCCNc2cc(Oc3ccc4c(C(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(F)cc5)cccc4c3)ncn2)CC1

Procedure:
100 mg (0.19 mMol) 6-(6-Chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-amide (Step 20.1) and 73 μl (0.42 mMol) 1-(3-aminopropyl)-4-methylpiperazine are dissolved in 5 ml EtOH. The reaction mixture is stirred at reflux for 30 h. It is worked up by removal of all volatiles under reduced pressure. The remaining crude product is purified by flash chromatography (combi-flash: 14 g column, CH2Cl2/MeOH; gradient 0-20% MeOH) to give the title compound as a yellow solid: m.p.: 131-133° C.
Reaction SMILES: [Cl-].[O:2]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[CH2:12][N+]1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]([CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O-:27])=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:27][CH2:12][C:11]1[CH:19]=[CH:20][CH:21]=[C:9]([O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=1)=[O:26])[CH3:23]
Reactant: c1ccc(Oc2cccc(C[n+]3ccccc3)c2)cc1
Reactant: CCC(C(=O)[O-])c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccccc1
Yield: 156.5 %

Procedure:
4.5 g of 3-phenoxybenzyl pyridinium chloride, 1.4 g of α-ethylphenyl-acetate and 50 ml of dimethylformamide were treated in the same manner as described in Example 1 to obtain 4.65 g of 3-phenoxybenzyl α-ethylphenyl-acetate (nD25 1.5715).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:19]([CH2:26][CH:27]([OH:31])[CH2:28][CH2:29]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>C(O)CCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[O:19]([CH2:26][CH:27]([OH:31])[CH2:28][CH2:29][N:16]1[CH2:17][CH2:18][N:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH2:14][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1cc(N2CCN(CCC(O)COc3ccccc3)CC2)cc(OC)c1OC
Yield: 58 %

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 2.5 g (0.01 mole) of 1-(3,4,5-trimethoxyphenyl)piperazine, 2.0 g (0.01 mole) of 1-phenoxy-4-chloro-2-butanol and 2.5 g (0.01 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave a red-brown gum as residue. The gum was converted to the oxalic acid salt and the salt was recrystallized from absolute ethanol to give 3.2 g (58%) of tan powder, m.p. 154°-156° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]=[S:22]1(=[O:28])[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:21]=[S:22]1(=[O:28])[CH2:26][CH2:25][CH:24]([NH:27][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC1CCS(=O)(=O)C1
Product: O=C(NC1CCS(=O)(=O)C1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 1,1-dioxidotetrahydrothien-3-ylamine (CAN 6338-70-1) as starting materials. MS (EI): m/e=402.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[C:8]([C:14]([O-])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[OH:15][C:14]1[C:23]2[C:18](=[C:19]([C:24]([F:25])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(=O)[O-])=C(Nc1ccccc1C(F)(F)F)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(-c2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Yield: 78.2 %

Procedure:
Using the procedure of Step D of Example 6, 31.56 g of the product of Step C and 32 ml of phenyl oxide were reacted to obtain 23.56 g of ethyl 4-hydroxy-2-phenyl-8-trifluoromethyl-quinoline-3-carboxylate melting at 114° C which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1.Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[N:10]=1)[CH2:19][O:20][C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)n3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(F)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(N[C@@H]2CCNC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.8 %

Procedure:
Crude (R)-tert-butyl 3-(5-fluoropyridin-2-ylamino)pyrrolidine-1-carboxylate (85 mg, 0.3 mmol) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL, 4 mmol) was added. The mixture was stirred overnight at rt and concentrated to afford crude (R)-5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine (76 mg, quant) which was used without further purification. LC-MS Method 1 tR=0.42 min, m/z=182.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:12]1[C:10]2[CH2:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1Cc2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2Cc3ccccc3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitrile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:26][O:27][CH2:28][C:29]#[CH:30].O>N1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:30]#[C:29][CH2:28][O:27][CH3:26])[CH:20]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: C#CCOC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: O
Product: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
A solution of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.65 g, 1.6 mmol) in pyrrolidine was treated with 3-methoxy-propyne (0.27 mL, 3.2 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (90 mg, 0.08 mmole), heated to 80° C. for 4 hrs, poured into water and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel in ethyl acetate to give the title product as a brown wax, 0.4 g (63% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C1(S[CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=3)[S:15]2(=[O:17])=[O:16])C=CC=CC=1.CCCCCC>ClCCl>[Cl:4][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=2)[S:15]1(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CSc1ccccc1)C2=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CCl)C2=O
Reaction time: 3 h
Yield: 87 %

Procedure:
Sulfuryl chloride (0.34 g) was added dropwise with stirring to a solution of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.96 g) in dichloromethane. Stirring was continued at room temperature for three hours and the solution was stripped of volatiles. Dichloromethane was added and the solution was stripped again. Hexane was added to the residue and the mixture was stirred at room temperature overnight. The resulting white solid was collected and dried affording 2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.69 g, 89% yield, mp 113°-115° C.).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[C:8]([NH2:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([NH:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:4]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1ccccc1
Product: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1

Procedure:
2,2,2-Trichloro-1,1-ethanediol and benzamide were processed as described in Example 37C to provide the desired product.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[C:21]([F:32])[C:20]=1[O:33][CH3:34]>>[NH2:31][C:28]1[N:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:20]([O:33][CH3:34])[C:21]=2[F:32])=[N:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Product: COc1c(-c2ccccc2S(=O)(=O)NC(C)(C)C)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared by a method analogous to Example 461 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C21H23FN4O3S, 430.15; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.53-8.48 (m, 1H), 8.19 (dd, J=7.9, 1.4, 1H), 8.08 (d, J=1.5, 1H), 7.64-7.55 (m, 2H), 7.52 (m, 1H), 7.29 (dd, J=7.4, 1.4, 1H), 7.18 (dd, J=8.2, 1.4, 1H), 4.80 (s, 2H), 4.42 (s, 1H), 3.85 (d, J=1.8, 3H), 1.21 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10]C)=O.[CH:12]1([C:15]#[N:16])[CH2:14][CH2:13]1.[NH4+].[OH-]>O1CCOCC1.O>[CH:12]1([C:15]2[N:16]=[C:8]([OH:10])[C:4]3[S:5][CH:6]=[CH:7][C:3]=3[N:2]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1sccc1N
Reactant: N#CC1CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1nc(C2CC2)nc2ccsc12
Yield: 72 %

Procedure:
Dry HCl gas was bubbled through a solution of methyl 3-aminothiophene-2-carboxylate (1.64 g, 10.4 mmol) and cyclopropanecarbonitrile (27 mL) in dioxane (40 mL) for 1 h then the reaction mixture was diluted with cold water (2 volumes), basified with NH4OH (50 mL) and the resulting solid filtered and air dried to give the title compound (1.44 g, 72%) as a white solid: IR νmax (Nujol)/cm−1 2925, 1664, 1597, 788; NMR δH (400 MHz, DMSO) 1.04 (4H, m), 2.00 (1H, m), 7.20 (1H, d J 5.0 Hz), 8.10 (1H, d, J 5.0 Hz) and 12.60 (1H,br).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH3:13])[NH:10]2)=[CH:6][CH:5]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH2:28]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH2:28][O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH3:13])[NH:10]2)=[CH:6][CH:5]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)CCl
Reactant: Cc1cc2ccc(O)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ccc(OCC(=O)NCCCCNC(=O)OC(C)(C)C)cc2[nH]1
Reaction time: 1 h
Yield: 156.3 %

Procedure:
1.07 g of sodium hydride in suspension in 50% of oil were added progressively to a solution of 3.28 g of 6-hydroxy-2-methyl indole in 50 ml of dimethylformamide and the suspension was stirred for one hour. A solution of 6.5 g of N'-(tertbutoxycarbonyl)-N-(chloroacetyl)-1,4-diamino-butane and 60 ml of dimethylformamide was slowly introduced. The reaction medium was stirred at 90° C. for 5 hours, then for 16 hours at ambient temperature. The suspension obtained was evaporated to dryness to obtain 13.08 g of a product which was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (30-70) to obtain 4.98 g of the sought product melting at 132° C.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.OC[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:2][C@@H:12]1[CH2:13][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CBr)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tetrabromomethane (1.23 g) was added to a solution of 1,1-dimethylethyl (3R)-3-(hydroxymethyl)-1-piperidinecarboxylate (500 mg) in methylene chloride (2.7 mL). The reaction mixture was cooled to 0° C. and a solution of triphenylphosphine (731 mg) in methylene chloride (2.7 mL) was slowly added. After 1 hour at 0° C., the reaction mixture was concentrated and directly purified by chromatography on silica gel eluting with heptane/ethyl acetate 1:15 followed 1:10 to yield the title compound as a slightly yellow oil (627 mg).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1C=CC=CC=1>CCOCC>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NCc1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NCc1ccncc1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.0 g. of 4-aminomethylpyridine in 100 ml. of benzene is refluxed for 24 hours. The reaction mixture is stripped of solvent and the residue dissolved in ether. The ether solution is washed with cold 5% sodium carbonate and water and dried over potassium carbonate and chromatographed with alumina and eluting with ether/hexane. The eluate is extracted with ether/acetone and concentrated in vacuo to give 4-pyridylmethyl-9-xanthylamine having a m.p. of 83°-85° C.