Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@@H:9]1[CH2:16][CH:17]=[CH2:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CP(C)C.O>C1COCC1>[C:1]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:16][CH:17]=[CH2:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CC[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a solution of (2S,4R)-1-Boc-2-allyl-4-azidopyrrolidine (450 mg, 1.78 mmol) prepared in Step B in THF was added dropwise trimethylphosphine (135 mg, 1.78 mmol). After the reaction mixture was stirred at rt for 5 h, water (0.03 ml) was added, and stirred for additional 20 min. The reaction mixture was concentrated in vacuo, extracted with EtOAc, washed with water and brine, and concentrated in vacuo. The residue was purified by column chromatography(eluent, MeOH/DCM=1/9) to give the title compound (280 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[CH:5]=[C:4]([NH2:24])[N:3]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:12][CH:11]=2)[C:5]([N:25]=[O:26])=[C:4]([NH2:24])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 76.9 %

Procedure:
Pyrimidine 37 (Example 20, 4.72 g, 13.7 mmol) is dissolved in 60 mL acetic acid (30%) and heated to 70° C. NaNO2 (1.4 g, 20.03 mmol) dissolved in 5 mL water is added drop wise until KJ-starch paper remains black. After cooling to 0° C. in an ice-bath, the purple precipitate is collected by filtration and recrystallized from acetone to yield 3.9 g (10.54 mmol, 77%) of a purple solid. 1H-NMR (400 MHz, DMSO-d6) δ=10.03 (d, J=4.0, 1H, 5-NHa), 10.00 (t, J=5.8, 1H, CF3CONH), 8.01 (d, J=4.0, 1H, 5-NHb), 7.86 (s, 1H, 1-NHa), 7.81 (s, 1H, 1-NHb), 7.51 (d, J=8.1, 2H, ArH), 7.30 (d, J=8.1, 2H, ArH), 5.54 (s, 2H, OCH2), 4.38 (d, J=5.8, 2H, CH2N) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:22])[C:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (7.28 g, 20.0 mmol, Intermediate 5: step a) in tetrahydrofuran (215 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 118.7 mL, 59.37 mmol) over 7 minutes. The mixture was stirred at −78° C. for 5 minutes and 0° C. for 1.5 hours. The resulting cold solution was quenched with water. The white solid formed was completely dissolved by addition of excess water. The aqueous phase was washed once with EtOAc and then acidified by slow addition of 2 N aqueous HCl solution (kept pH above 2). The off-white precipitate formed was filtered and dried in the air overnight and at 40° C. for 1 hour to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[CH:3]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[C:5]([CH2:9][CH2:10][C:11]2=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)CCc1cc(F)c(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2c(F)cc(Br)c(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(4-bromo-2,5-difluorophenyl)propanoic acid (1.10 g) in DCM (20 mL) was added SOCl2 (2.45 g). The mixture was stirred at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The residue was dried under high vacuum to give a crude solid. To the residue was added AlCl3 (2.76 g) and the mixture heated to 130° C. The mixture was stirred at 130° C. for 2 hours and then cooled to room temperature. The resulting mixture was treated with ice water and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (5:1) to give the subtitle compound as a light yellow solid. MS ESI+: m/z=247 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=[C:3]([F:29])[CH:4]=1)[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cscn2)c(F)c1
Yield: 77.1 %

Procedure:
A mixture of 5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide (450 mg, 0.912 mmol), 4-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred at reflux for 17 h. After cooling, the mixture was diluted with ethyl acetate, washed with water. The organic layer was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:3/1:2) to afford 350 mg (77.1%) of the titled compound as a yellow solid.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[CH3:8][N:9]1[C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:13]2=[CH:14][CH:15]=[CH:16][N:12]2[CH2:11][CH2:10]1.CN(C)C=O>O1CCCC1>[C:6]([C:16]1[N:12]2[CH2:11][CH2:10][N:9]([CH3:8])[C:17]3([CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[C:13]2=[CH:14][CH:15]=1)#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
A solution of chlorosulfonyl isocyanate (590.9 mg, 363.4 μL, 4.175 mmol) in tetrahydrofuran (2 mL) was slowly added to a solution of tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1020 mg, 3.340 mmol) in tetrahydrofuran (9 mL) held at −78° C. (bath temperature) under an atmosphere of argon. The reaction mixture was allowed to stir for 1 hour at −78° C. N,N-dimethylformamide (732.4 mg, 775.8 μL, 10.02 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. After stirring for 3 hours at room temperature the crude material was diluted with 25 mL of tetrahydrofuran, washed with a 1M solution of sodium hydroxide, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified on 80 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes to yield tert-butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (280 mg, 25%) as a white solid. ESI-MS m/z calc. 330.2, found 331.1 (M+1)+; Retention time: 0.94 minutes. 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=4.0 Hz, 1H), 5.97 (d, J=4.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.98-3.76 (m, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.30-3.08 (m, 2H), 2.36 (s, 3H), 2.09-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O=S(Cl)Cl.[CH3:15]O>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)nc1

Procedure:
A solution of 6-methyl nicotinic acid, 2-1 (5 g, 36.5 mmol) in 100 ml of anhydrous methanol was placed in a 250 ml three neck flask equipped with a dropping funnel vertical condenser and CaCl2 drying tube. The reaction solution was cooled to -15° in an ice acetone bath and SOCl2 (5 ml, 69.1 mmol) was added dropwise. The solution was then heated at reflux for 3 h then cooled and the solvent removed at reduced pressure. The resulting white solid was treated with 60 ml of saturated NaHCO3 and extracted into CH2Cl2 (3×50 ml). The pooled extracts were dryed (Na2SO4 ), filtered and evaporated at reduced pressure. The resulting oil crystallized on standing giving 2-2 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:10][C:11](=O)[CH2:12][C:13]([CH2:15][Cl:16])=O)C>>[CH:6]1[CH:5]=[CH:4][N:3]2[C:2](=[N:1][C:13]([CH2:15][Cl:16])=[CH:12][C:11]2=[O:10])[CH:7]=1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2ccccn12
Temperature: 120 °C
Yield: 98.9 %

Procedure:
15 g (159.4 mmol) of 2-aminopyridine was combined with approximately 80 g of polyphosphoric acid and heated to 120° C. to allow stirring. To the resulting solution was added slowly 30.5 mL (223.2 mmol) of ethyl-4-chloroacetoacetate and stirred at 120° C. under nitrogen for two hours. The hot reaction mixture was then poured over 1500 mL of ice water and stirred vigorously. The aqueous layer was separated and extracted with methylene chloride (6×, approximately 6 L). The combined organic layers were washed with saturated NaHCO3 and brine and dried over MgSO4 and activated carbon. The solvent was removed in vacuo yielding 30.7 g (157.7 mmol, 99%) of 2-(chloromethyl)-5-hydropyridino[1,2-a]pyrimidin-4-one as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](O)(=[O:33])/[CH:30]=[CH:31]/[CH3:32]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:29](=[O:33])/[CH:30]=[CH:31]/[CH3:32])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: C/C=C/C(=O)O
Product: C/C=C/C(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 72 %

Procedure:
(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and (E)-but-2-enoic acid using Method E (72% yield). HPLC: 95%, RT=4.079 min. MS: m/z=437 [M+H]+, RT=4.07 min. 1H-NMR (DMSO-d6) δ 8.51 (s, 1H), 8.42-8.39 (m, 2H), 7.53-7.52 (m, 2H), 7.43-7.37 (m, 3H), 7.28 (d, 1H), 7.19 (d, 2H), 7.14 (t, 1H), 7.08 (d, 2H), 7.02 (d, 2H), 6.78 (d, 1H), 6.63 (qd, 1H), 5.94 (d, 1H), 4.38 (d, 2H), 1.76 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39](Cl)=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:23])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cc(C)n(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (0.62 mmol) in acetonitrile (5 mL), was treated with potassium carbonate (1.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (0.68 mmol), before being heated to 120° C. in a microwave reactor for 4.5 hours. The mixture was evaporated in vacuo, before being partitioned between DCM (20 mL) and water (20 mL). The organics were evaporated in vacuo then chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (160 mg).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].Cl.[C:7]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:23])=[CH:11][CH:10]=1)#[N:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:23][S:2]([OH:5])(=[O:4])=[O:3])=[CH:33][CH:34]=1)#[N:8]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](N)Cc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](Cc2ccccc2)NS(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
0.58 g (0.33 ml, 5 mmol) of chlorosulfonic acid in 10 ml of DCM was slowly added dropwise at 20° C. with cooling to a solution of 1.8 g (4.36 mmol) of D-phenylalanylproline (p-cyanobenzyl)amide hydrochloride and 1.68 g (13.0 mmol) of diisopropylethylamine in 20 ml of DCM. After stirring at room temperature for 30 min, the mixture was diluted to 100 ml with DCM and extracted initially with 2M HCl and then twice with 10 ml of water, and the organic phase was dried over magnesium sulfate and evaporated in a rotary evaporator. 2.0 g of N-hydroxysulfonyl-D-phenylalanylproline (p-cyanobenzyl)amide were obtained as crude product which was used for the next reaction without further purification.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2cccnc2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2cccnc2)s1
Yield: 79.1 %

Procedure:
A mixture of 2-acetylamino-5-(3-pyridylthio)thiazole (8.5 g) in a mixture of ethanol (160 ml), tetrahydrofuran (50 ml) and aqueous 6N hydrochloric acid (100 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(3-pyridylthio)thiazole (5.6 g yield: 78.9%). mp: 140°-142° C. IR (Nujol): 3400, 3300, 3125, 1630, 1530, 1490 cm-1
Reaction SMILES: P(=O)(O)(O)O.[I-:6].[K+].[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12]O>>[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12][I:6]
Reactant: CC(CCO)C(F)(F)F
Reactant: [I-]
Agent: O=P(O)(O)O
Agent: [K+]
Product: CC(CCI)C(F)(F)F
Temperature: 0 °C

Procedure:
To a mixture of 19 g phosphoric acid (98%) and 19 g potassium iodide are added at 40° under stirring 4.75 g (33.4 mMol) of 4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. The mixture is then heated at 120° for 16 hours, a cooling poured into ice-water and extracted with diethylether. The etheric extracts are washed with 10% sodium thiosulfate and brine acid dried over sodium sulphate. After filtration, the solvent is removed through a 15 cm Vigreux-column at atmospheric pressure, followed by fractionation giving 4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76°-77° at 140 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH3:18])[CH:6]=1)=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH2:18][Br:37])[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 191 mg (0.73 mmol) of 4′-chloro-2-methyl-biphenyl-4-carboxylic acid methyl ester in 4 mL of carbon tetrachloride (CCl4) was added 9.7 mg (0.04 mmol) of benzoyl peroxide, followed by 124 mg (0.696 mmol) of N-bromosuccinimide (NBS), and the reaction mixture was heated at reflux for 6 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give 132 mg (53%) of 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester, as an oil, which was used without any further purification in the next step. 1H NMR δ CDCl3 8.10 (s, 1H), 7.91–7.89 (d, J=8.0 Hz, 1H), 7.37–7.35 (d, J=8.3 Hz, 2H), 7.30–7.18 (d, J=8.7 Hz, 2H), 7.22–7.20 (d, J=8.0 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: C(N=C=O)(C)(C)C.[C:8]([NH:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38]C)=[C:33]([O:40][CH2:41]C)[CH:32]=3)[C@@H:28]3[C@@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22]2=[O:43])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([NH:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:40][CH3:41])[CH:32]=3)[C@@H:28]3[C@@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22]2=[O:43])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: CC(C)(C)N=C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and t-butylisocyanate as described for compound 6. Crystallisation from ether. M.p. 164-166° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].Cl>O.ClCCl>[Br:15][CH2:16][C:17]([NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:18]
Reactant: Cc1cncc(N)n1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1cncc(NC(=O)CBr)n1

Procedure:
6-Methyl-pyrazin-2-ylamine (150 mg) and potassium carbonate (571 mg) were added to dichloromethane (25 mL). 2-Bromoacetyl bromide (0.120 mL) was added to the suspension with stirring. The reaction was stirred overnight then water (0.1 mL) was added with further stirring. Further quantities of potassium carbonate (571 mg), 2-bromoacetyl bromide (0.120 mL) and water (0.1 mL) were added over 2 hours until the reaction had proceeded to completion. The reaction was diluted with water (100 mL), carefully acidified with hydrochloric acid and extracted with dichloromethane (2×50 mL) which was dried and evaporated to afford the sub-titled compound which was used crude (365 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][N:1]2[CH3:16])=[CH:5][CH:6]=1)=[O:11]
Reactant: CI
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 6-indolecarboxylate (5 g) in dry dimethylformamide (30 ml) cooled to 5° C., sodium hydride (60% dispersion in oil, 1.49 g) was added portionwise. The reaction mixture was stirred at 5° C. for 0.5 hour, then a solution of methyliodide (12.18 g) in dry dimethylformamide (10 ml) was added dropwise. After 2 hours, the reaction mixture was diluted with water and the product obtained, after cooling and filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>O>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][OH:20]
Reactant: CNCCCO
Reactant: Brc1ccn2c(n1)nc1ccccc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.2 %

Procedure:
2-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), 3-(methylamino)propan-1-ol (0.072 g, 0.806 mmol) and N,N-Diisopropylethylamine (0.141 ml, 0.806 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated to afford crude 3-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl(methyl)amino)propan-1-ol (0.207 g, 0.808 mmol, 100% yield).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(O)=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+].C(OC(=O)C)(=O)C>O>[C:20]([O:15][C:13]1[C:6]2[CH:7]=[C:8]([Cl:10])[CH:9]=[CH:4][C:5]=2[S:11][C:12]=1[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCc1sc2ccc(Cl)cc2c1OC(C)=O
Temperature: 80 °C

Procedure:
A mixture of 2-(2'-carboxy-4'-chlorophenylthio)hexanoic acid (2.3 g, 7.6 mmol), anhydrous sodium acetate (1.0 g), and acetic anhydride (5 ml) was heated at 80° C. for 30 minutes. After gas evolution had ceased, the temperature was gradually raised to 120° C. which was maintained for 30 minutes. The cooled reaction mixture was then poured into water and extracted with diethyl ether. The combined ethereal extracts were washed with 1% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734) eluting with 25:1 hexane-ether to give 3-acetoxy-2-butyl-5-chlorobenzo[b]thiophene as a colorless oil; yield 1.1 g (40% overall from the 2-step sequence), m/z 282 (M+.).
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([NH:11][CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9].Cl[CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19]>C(N(CC)CC)C>[CH:8]([NH:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19])([CH3:10])[CH3:9]
Reactant: CC(C)NCCN
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CCNCCNC(C)C
Yield: 63.2 %

Procedure:
Three hundred milliliters of a toluene solution of a mixture of N-isopropyl-1,2-ethylenediamine (20.0 g), 3-chloro-2',6'-dimethylpropionanilide (13.9 g) and triethylamine (10 ml) is treated as in Example 1 to provide a pale yellow powder. Recrystallization from n-hexane provides a colorless needle in an amount of 11.5 g (yield: 63.2%). m.p. 69.5° C.