Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([Br:16])[C:6]1=[O:17])(=O)C.BrC1C(=O)[C@@H]2OC[C@H](C=1)O2.O.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[C:13]([O:12][CH2:11][C@H:9]1[O:10][CH:5]([OH:4])[C:6](=[O:17])[C:7]([Br:16])=[CH:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C=C(Br)C(=O)[C@@H](OC(C)=O)O1
Agent: O=C1C(Br)=C[C@H]2CO[C@@H]1O2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1C=C(Br)C(=O)C(O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
200 mg of 1,6-di-O-acetyl-3-bromo-3,4-dideoxy-α-D-glycero-hex-3-enopyranos-2-ulose prepared in the same manner as in the above Intermediate Preparation Example 4 from 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 4) prepared by the method disclosed in Carbohydrate Research (1981), Vol. 93, 284-287, was dissolved in 6 ml of tetrahydrofuran-water (5:1), and 70 mg of lithium hydroxide monohydrate was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 100 ml of ethyl acetate was added. The mixture was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by thin layer chromatography for separation (NO-5744, manufactured by Merck, ethyl acetate: hexane=1:1) to obtain 40 mg of the desired product (Intermediate No. 18) as a slightly yellow liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:29]([Si:32](Cl)([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Reaction time: 0.17 h

Procedure:
To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1901, 560.0 mg, 1.60 mmol, prepared as described in Example 18, Scheme 33) in tetrahydrofuran (28.0 mL) was added sodium hydride (100.0 mg, 60% in mineral oil, 2.50 mmol). After 10 minutes, triisopropylsilyl chloride (0.500 mL, 2.36 mmol) was added to the reaction. After 4 hours, the reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (602, 0.70 g, 86.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(C)C=CC=CC=1>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-(3-(5-bromopyrimidin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.285 g, 0.629 mmol) was suspended in dichloromethane (4 mL) and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature for 3 h. Toluene was added and the reaction was concentrated in vacuo. After evaporating again from toluene, the residue was dried in vacuo to afford the title compound (0.385 g, quantitative yield based on 2.3 eq trifluoroacetic acid) as an orange oil. This material was dissolved in acetonitrile (3 mL) and used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][CH2:14][Br:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cc1ccc(OCCCBr)cc1
Yield: 82.1 %

Procedure:
This compound was produced using similar methods as those used Step 3, example 6, starting with (4-hydroxy-phenyl)-acetic acid methyl ester (5.00 g, 30.1 mmol), 1,3-dibromopropane (24.3 g, 120 mmol) and cesium carbonate (40.3 g, 120 mmol). The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give [4-(3-Bromo-propoxy)-phenyl]-acetic acid methyl ester (7.10 g, 82%) as a faint-yellow oil. 1H NMR (400 MHz, DMSO-d6); δ 7.15 (d, 2H), 6.87 (d, 2H), 4.03 (t, 2H), 3.63 (t, 2H), 3.58 (s, 3H), 3.57 (s, 2H), 2.21 (m, 2H).
Reaction SMILES: COC([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=O.N.ClCCl>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A solution of compound 5 (5.25 g, 0.014 mol) and aqueous ammonia (35% w/v, 100 ml) in ethanol (200 ml) was stirred for 1 h at room temperature. TLC analysis (dichloromethane) revealed a complete reaction. The solvent was removed in vacuo and the shite solid was recrystallised from ethanol to give colourless crystals.
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:7][NH:6][CH2:5]1)#[N:3].N1CCCC1.CC(O[C:18]([NH:20][C@@H:21]([C:28]([OH:30])=O)[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:19])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:47][N:48]1[CH:52]=[C:51]([C:53]2[N:58]=[C:57]3[C:59](C(O)=O)=[CH:60][N:61](COCC[Si](C)(C)C)[C:56]3=[N:55][CH:54]=2)[CH:50]=[N:49]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[C:2]([CH:4]1[CH2:7][N:6]([C:28](=[O:30])[C@H:21]([NH:20][C:18]([C:59]2[C:57]3[C:56](=[N:55][CH:54]=[C:53]([C:51]4[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=4)[N:58]=3)[NH:61][CH:60]=2)=[O:19])[CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:5]1)#[N:3]
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: N#CC1CNC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(C#N)C4)C4CCCCC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3-cyanoazetidine hydrochloride for pyrrolidine, Boc-D-cyclohexyl glycine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used in place of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=447.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:8]=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].C([Mg]Cl)(C)(C)C>[Ni](Br)Br.O1CCCC1>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: c1ccncc1
Reactant: Cc1ccccc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Br[Ni]Br
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a nitrogen purged three-neck 100 mL flask was added nickel(II) bromide (0.22 grams, 1 mmole), polyvinyl pyridine (0.63 grams of Reillex® 402 obtained from Reilly Tar and Chemical Company, Indianapolis, IN), triphenylphosphine (2.62 grams, 10 mmole), 2-chlorotoluene (2.53 grams 20 mmole) and tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 5 minutes and then tertiary-butylmagnesium chloride (12 mL of 2.0 Molar solution in THF, 24 mmole) was added dropwise over a 10 minute period. The reaction warmed upon addition and at the end of the addition was heated to reflux for 14 hours. The mixture was cooled to ambient and analyzed by conventional gas chromatographic methods. The results of the reaction are:
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[CH2:7][N:4]1[C:5](=[O:6])[C@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@H](N)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reaction time: 0.75 h

Procedure:
The amino compound from Example 3 (4.22 g, 11 mmol) was dissolved in ethyl acetate (60 ml) and cooled in an ice-alcohol bath. Triethylamine (1.67 g, 16.5 mmol) was added, followed by the dropwise addition of phenoxyacetyl chloride (2.06 g, 12.1 mmol) over a period of 5 minutes. The reaction was stirred for 45 minutes with cooling and then filtered. The filtrate was washed with 5% NaHCO3 and brine. The dried filtrate was evaporated to give the title product; 2.0 g. The product was recrystallized from ethyl acetate-ether; 1.02 g, mp 137-138°. The solid which was filtered from the reaction solution was stirred with hot ethyl acetate (100 ml) and filtered. The filtrate was treated with ether (200 ml) and cooled to give additional product; 3.91 g, mp 138-139°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].CCN(CC)CC>C(Cl)Cl>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=3)=[O:31])[C:3]=2[CH3:18])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(N)cccc1C(=O)Nc1cnc(N)nc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cccc(C(F)(F)F)c2)cccc1C(=O)Nc1cnc(N)nc1

Procedure:
3-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 42 (113 mg, 0.464 mmol) [prepared according to the procedure described for methylbenzamide5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide in Example 1] was taken up in CH2Cl2 (4 mL) and pyridine (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.31 mL, 2.09 mmol) was added followed by NEt3 (0.13 mL, 0.928 mmol). Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the product purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 97% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 43 as an off-white solid. MS m/z found 416 [MH+]; calc. for C20H16F3N5O2=415.13; and 2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-5-pyrimidinyl)benzamide 44 as an off-white solid. MS m/z found 588 [MH+]; calc. for C28H19F6N5O3=587.14.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](N)=[CH:4][C:5](OC)=[O:6].[CH3:12][NH:13][NH2:14].Cl>O>[CH3:12][N:13]1[C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][C:5]([OH:6])=[N:14]1
Reactant: CNN
Reactant: COC(=O)C=C(N)C(F)(F)F
Agent: Cl
Solvent: O
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 50 °C
Yield: 76 %

Procedure:
A mixture of 33.82 g (0.20 mole) of methyl 4,4,4-trifluoro-3-amino-2-butenoate and 10.1 g (0.22 mole) of methylhydrazine was heated at 50° C. for 22.25 hr. The mixture was then cooled, and 15 ml. of water and about 12 ml. of conc. hydrochloric acid were added to bring the pH of the mixture to 6.5-7.0. The precipitated product was filtered off and dried to obtain 25.26 g (76% yield) of the product m.p. 130.5°-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:36][C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[N:34][CH:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:36][C:32]([CH2:30][CH3:31])=[CH:33][N:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191.5 mg; compound B26) and HBTU (167 mg) in DCM (3 ml) is added DIPEA (0.28 ml) and the mixture is stirred for 1 h at RT. After 1 h an additional amount of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (40 mg) is added and the mixture is stirred for 15 min in order to complete the reaction. Subsequently the solvent is removed and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][CH2:25][O:24]1>C(OC(=O)C)C>[Br-:20].[O:24]1[CH2:25][CH2:26][CH2:27][O:28][CH:23]1[CH2:22][CH2:21][N+:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C=Cc2ccnc3ccccc23)cc1
Reactant: BrCCC1OCCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C=Cc2cc[n+](CCC3OCCCO3)c3ccccc23)cc1
Product: [Br-]
Yield: 70 %

Procedure:
4-(4-methylstyryl)quinoline (0.245 g) and 2-(2-bromoethyl) 1,3-dioxane (0.195 g) were mixed and refluxed in ethylacetate (1.5 ml) for 18 hours. Yellow-green precipitate was separated by filtration, washed with ethyl ether and dried in vacuo to give 0.308 g of N-[2-(1,3-dioxane-2-yl)ethyl]-4-(4-methylstyryl)-quinolinium bromide.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].N[CH:10]([OH:12])[CH3:11].C([N:15](CC)CC)C>C1COCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH:15][CH2:11][CH2:10][OH:12])=[O:5])[CH3:2]
Reactant: CC(N)O
Reactant: CCN(CC)CC
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)NCCO
Temperature: 25 °C
Reaction time: 60 h

Procedure:
N,N-Diethylcarbamyl chloride (8.2 g, 0.06 mole) in THF (15 ml) was added dropwise to a solution of aminoethanol (3.08 g, 0.05 mole), triethylamine (6.08 g, 0.06 mole) and THF (25 ml) at 0° C. The mixture was stirred at room temperature for 60 hrs., filtered and concentrated to 9.0 g of N,N-diethyl-N'-hydroxyethyl urea as a pale yellow oil; nmr (CDCl3) δ1.15 (t, 3H), 2.88-3.84 (m, 8H), 5.26 (s, broad, 1H), ir (neat) 3380, 1620 Cm-1.
Reaction SMILES: [NH4+].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10](Cl)[C:11]=1[Cl:12])[C:6]([O-:8])=[O:7].[CH3:17][O-:18].[Na+].[CH3:20]O>CN(C)C=O>[CH3:20][O:8][C:6](=[O:7])[C:5]1[C:9]([Cl:14])=[C:10]([O:18][CH3:17])[C:11]([Cl:12])=[C:3]([Cl:2])[C:4]=1[C:15]#[N:16]
Reactant: CO
Reactant: C[O-]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(OC)c(Cl)c(Cl)c1C#N
Reaction time: 15 h

Procedure:
30.2 g of 3,4,5,6-tetrachloro-2-cyanobenzoic acid ammonium salt is introduced, with stirring, into a solution of 10.8 g of sodium methylate in 32 ml of methanol and 100 ml of dimethylformamide. After the slightly exothermic reaction has subsided, stirring is continued for 15 hours at room temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19](Br)=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19]([C:31]#[N:32])=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(-c2cscc2Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1cc(-c2cscc2C#N)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution (5 mL) of tert-butyl{[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (470 mg) in N,N-dimethylformamide were added zinc cyanide (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was sufficiently degassed. The mixture was stirred with heating at 120° C. for 18 hr and cooled to room temperature. Water and ethyl acetate were added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 297 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.[C:31]([Mg]Br)#[CH:32]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:31]#[CH:32])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step B (93 mg, 0.21 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium bromide, 0.5M in tetrahydrofuran, (0.62 mL, 0.31 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13].Cl>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C#N
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifluoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6-lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric acid (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
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.[CH3:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:24]3[CH2:23][O:22][CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COC[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (R)-2-(methoxymethyl)pyrrolidine (84025-81-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].