Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH2:18]([N:25]([CH2:31]O)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([N:25]1[CH2:31][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Reactant: CCOC(=O)/C=C/C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C1CC1
Yield: 56 %

Procedure:
To a stirred solution of ethyl (2E)-3-cyclopropylacrylate (5.3 g, 37.9 mmol) and TFA (0.43 g, 3.79 mmol) in DCM (100 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (13.5 g, 56.8 mmol) at 0° C. After the addition, the mixture was refluxed overnight. TLC (petroleum ether: EtOAc 10:1) indicated most of ethyl (2E)-3-cyclopropylacrylate was consumed. The reaction mixture was quenched with sat. NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=50:1 to 30:1) to give the title compound (5.8 g, 54% yield) as a yellow oil.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]2[N:15]([CH2:25][CH3:26])[C:16](=[O:24])[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:13]=2[CH:12]=1)C>O>[CH2:25]([N:15]1[C:16](=[O:24])[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([OH:29])=[O:7])[CH:28]=[CH:27][C:14]1=2)[CH3:26]
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
50% Sodium hydroxide aqueous solution (1 ml) was added to a methanol (20 ml) solution of 3-(1-ethyl 3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) propionic acid ethyl ester (1.1 g). The mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by washing with ether. A hydrochloric acid was added to the aqueous layer, followed by extraction using ethyl acetate and drying using magnesium sulfate. The dried product was condensed under reduced pressure to give the title compound (0.97 g) as a colorless oily matter.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH3:30][CH:31]([CH3:36])[CH2:32][CH2:33]C=O>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:33][CH2:32][CH:31]([CH3:36])[CH3:30])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC(C)CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(C)C

Procedure:
The product of Example 100 is treated with 4-methylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:28][CH2:27]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][N:40]=[C:32]([N:29]4[CH2:28][CH2:27][O:26][CH2:31][CH2:30]4)[CH:33]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccnc(N2CCOCC2)c1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-morpholin-4-yl-isonicotinamide was prepared starting from intermediate A and 2-morpholinoisonicotinic acid. MS calcd. for C29H25ClN5O4 [(M+H)+] 542.2, obsd. 542.2.
Reaction SMILES: CO[CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][O:12][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)[P:14]([O:18][CH2:19][CH3:20])(=[O:21])[O:15][CH2:16][CH3:17]
Reactant: COc1cccc(C(OC)OC)c1
Reactant: CCOP(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cccc(OC)c1
Reaction time: 15 h

Procedure:
m-Methoxybenzaldehyde dimethyl acetal from Example 4 (271.4 g, 1.49 mol), triethyl phosphite (250.3 g, 1.51 mol), and methylene chloride (600 ml) were charged into a 3 liter 3-necked flask which was outfitted with a dropping funnel, an argon inlet, and an argon outlet. The flask was flushed with argon and the funnel was capped with a septum. The mixture was stirred and cooled to -40° in a liquid nitrogen-acetone bath. Boron trifluoride etherate (198.1 ml, 1.61 mol) was then added dropwise from the funnel over a 25 minute period. The mixture was allowed to slowly warm up to 5° over 3 hours. Stirring was then continued at room temperature for another 15 hours. The light yellow solution was then stirred rapidly as 500 ml saturated sodium bicarbonate solution was added. After 1 hour the mixture was transferred to a separatory funnel. The organic layer was isolated and washed with 500 ml water, 2×300 ml saturated sodium bisulfite, and 300 ml saturated bicarbonate solution. Drying was accomplished over 30 g anhydrous sodium sulfate just before decolorizing carbon (3 g) was added to the solution, and the whole was filtered under vacuum through celite. Concentration on the rotory evaporator and high vacuum pumping to a final pressure of 0.15 mm Hg at 100° C. provided a light yellow oil weighing 380 g (90%). I.R. (neat, cm-1): 2974, 1596, 1582, 1480, 1255 (P=O ), 1098, 1050, 1020, 965, 1HNMR (400 MHz, CDCl3): δ1.21 and 1.25 (6H, two t, 7 Hz, OCH2CH3); 3.37 (3H, s, ArCHOCH3); 3.80 (3H, s, ArOCH3); 3.90-4.10 (4H, m, OCH2CH3); 4.46 (1H, d, 15.6 Hz, ArCHPO); 6.85 (1H, m); 7.00 (2H, m), 7.26 (1H, m). This product was sufficiently pure for use in a Horner-Emmons reaction. However, further purification to remove a trace of a non-polar fluorescent impurity may be accomplished with silica gel chromatography using dichloromethane to elute the impurity and subsequent elution with 20% ethyl acetate in dichloromethane to elute the phosphonate. ##STR29##
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:108]
Reactant: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C)C[C@@H]1c1ccccc1
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN2C(=O)C=CC2=O)C(C)C)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mg (12 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-(ethoxycarbonyl)-2-phenylcyclopropyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3 ml of DMF and then admixed with 8.9 mg (23 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 10 μl of N,N-diisopropylethylamine and with 12 mg (47 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 5.8 mg (37% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[N:6][C:5]=1[Cl:12].[CH:14]([NH2:16])=[O:15].[CH:17](N)=[O:18].[Na]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH:17]=[O:18])[CH:14]=[O:15])=[N:6][C:5]=1[Cl:12]
Reactant: NC=O
Reactant: COC(=O)c1ccc(CBr)nc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C=O)C=O)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of crude 6-bromomethyl-2-chloronicotinic acid methyl ester (<138 g, <0.54 mol) in DMF (400 mL) was added sodium diformamide (56.3 g, 0.59 mol) and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture rapidly darkened and a small exotherm was observed. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL). The resultant solution was washed with water (400 mL) and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was dry-loaded onto silica (150 g) and the residue subjected to flash chromatography (SiO2 400 g, 40% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (46 g, 33% over two steps). 1H NMR (CDCl3, 400 MHz) 8.46 (2H, br s), 7.56 (1H, d, J=7.7 Hz), 6.66 (1H, d, J=7.9 Hz), 4.39 (2H, br s), 3.36 (3H, s).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.O>[C:13]([O:12][C:10]([N:1]1[CH:5]2[CH2:6][N:7]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2CCNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2CCN(CCCCl)CC21
Yield: 75 %

Procedure:
To a solution of tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.21 g) in acetone (15 mL) was added K2CO3 (3.00 g) and 1-bromo-3-chloropropane (1.6 mL). The reaction mixture was heated to reflux for 7 h, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow liquid (1.20 g, 75.00%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[N:7]([CH2:20][CH2:21][OH:22])[CH:6]=[CH:5]2.[Br:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([CH3:34])[CH:31]=[C:32](I)[C:25]=12>>[Br:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([CH3:34])[CH:31]=[C:32]([C:10]3[CH:9]=[C:8]4[C:4]([CH:5]=[CH:6][N:7]4[CH2:20][CH2:21][OH:22])=[CH:3][C:2]=3[F:1])[C:25]=12
Reactant: CC1(C)OB(c2cc3c(ccn3CCO)cc2F)OC1(C)C
Reactant: Cn1cc(I)c2c(Br)ccnc21
Product: Cn1cc(-c2cc3c(ccn3CCO)cc2F)c2c(Br)ccnc21

Procedure:
The title compound was prepared from 2-(5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanol (D79) and 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) using a similar procedure to that described for D8. LCMS (A): m/z (M+H)+ 388/390, C18H15BrFN3O requires 387/389 (acidic).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24](=[CH:30]O)[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24](=[CH:30][NH:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:17][CH:16]=3)[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: Nc1ccc(OCCCCN2CCCCC2)cc1
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCCCN2CCCCC2)cc1
Yield: 72.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(4-piperidin-1-yl-butoxy)-phenylamine (400 mg, 1.1 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (263 mg, 1.47 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (435 mg, 73%).
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]1([C:17]#[C:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:3]1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Sc1c[nH]c2ccccc12
Product: O=C(O)C=Cc1cccc(Sc2c[nH]c3ccccc23)c1

Procedure:
By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and phenylpropiolic acid gives 20.0 g of product after recrystallization and acetone-water, mp 165°-167° C.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:15]C)(=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Na]>CO>[C:10]([O:12][CH2:13][C:5]1[O:6][CH:2]=[CH:3][CH:4]=1)(=[O:11])[CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: COC(=O)CC(=O)OC
Reactant: OCc1ccco1
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
196 parts by wt. of furfuryl alcohol and 132 parts by wt. dimethyl malonate (stoichiometric proportions) are mixed and 0.5-0.75% wt. sodium metal added. The mixture is heated to a temperature in the range from 214°-240° F. under a nitrogen atmosphere. Methanol is evolved and removed as the reaction progressed. After a period of 4 hours, a waxy solid is obtained. The liquid product obtained after washing with water is difurfuryl malonate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=1)[C:15]#[N:16]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].O>[Br:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:17][C:14]=2[C:15]#[N:16])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)ccc1-c1cncc(Br)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3,5-dibromopyridine (1.0 g, 4.2 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.95 g, 3.8 mmol) in 1,2-dimethoxyethane (20 ml) and 2N sodium carbonate solution (10 ml) was degassed with nitrogen for 30 min. Tetrakis-(triphenylphosphine)palladium(0) (89 mg, 0.08 mmol) was added and the mixture heated under reflux for 18 h. The mixture was allowed to cool to ambient temperature, diluted with water (10 ml) then extracted with ethyl acetate (2×100 ml). The organics were combined, dissolved in phophorus oxychloride (50 ml) and heated at 100° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was treated with ice, and the resulting solution was layered with ethyl acetate (30 ml) and made basic by the addition of solid sodium hydrogencarbonate. The layers were separated, and the aqueous extracted further with ethyl acetate (75 ml). The organics were combined, washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a colourless oil. The oil was purified by flash column chromatography on silica, eluting with isohexane on a gradient of ethyl acetate (20-50%), to give 2-(5-bromopyridin-3-yl)-5-fluorobenzonitrile (0.95 g, 81%) as a white solid: δH (360 MHz, CDCl3) 7.44-7.46 (1H, m), 7.49-7.54 (2H, m), 8.02 (1H, s), 8.67 (1H, d, J 1.8), 8.78 (1H, d, J 1.8).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCN(S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 59 %

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 89.1, Isomer 1) (100 mg, 0.21 mmol) was dissolved in dichloromethane (2.5 ml) and diisopropylethylamine (54 μl, 0.31 mmol) added. Methanesulfonyl chloride (19 μl, 0.25 mmol) was added and the mixture stirred for 1 hour, absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. The appropriate fractions were concentrated and the residues purified by column chromatography on silica, eluting with methanol/dichloromethane (2/98) to give the title product (Isomer 1) (70 mg, 60%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.67 (m, 1H); 1.92 (m, 2H); 2.07 (m, 1H); 2.21 (s, 3H); 2.66 (d, 3H); 2.88 (s, 3H); 3.03 (m, 1H); 3.21 (m, 1H); 3.34 (d, 1H); 3.52 (d, 1H); 3.62 (d, 1H); 3.79 (d, 1H); 3.96 (s, 3H); 7.20 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.62 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.57 (s, 1H). Mass Spectrum: (M+H)+ 565.5
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([N:3]1[C:2]([NH2:1])=[C:6]([C:7]#[N:8])[CH:5]=[N:4]1)[CH:10]=[CH2:9]
Reactant: N#Cc1c[nH]nc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc(C#N)c1N
Temperature: 80 °C
Yield: 39.8 %

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 1.08 g, 10.0 mmol), allylbromide (Acros, 1.45 g, 12 mmol) and anhydrous potassium carbonate (Fisher, 1.65 g, 12 mmol) were suspended in 10 mL anhydrous DMF and heated at 80° C. under argon overnight. The solution was concentrated. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded a solid which was subjected to flash chromatography on silica gel (gradient elution 2:1 to 3:2 hexane: ethyl acetate). 589 mg (40%) of a white solid was obtained which was seen by NMR to contain an inseparable mixture of 5 and 6 in a 2.1:1 ratio. This mixture was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22].[SH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: Sc1ncc[nH]1
Reactant: O=C(Nc1cccc2c(Cl)c(Br)cnc12)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc2c(Sc3ncc[nH]3)c(Br)cnc12)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromo-4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (120 mg) in N-methylpyrrolidone were added 2-mercaptoimidazole (33.5 mg) and potassium carbonate (50.1 mg), and the mixture was stirred for 40 minutes at ambient temperature, for 1 hour at 40° C., for 1 hour at 80° C. and for 1 hour at 90° C. To the mixture was added water, and the resulting precipitate was collected by filtration and washed with water and ethanol to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(imidazol-2-ylthio)quinoline (88.0 mg).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:5][C:6](=[O:21])[C@@H:7]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[OH-].[Li+]>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CC(C)(C)C)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
N-(tert-Butoxycarbonyl)-3-tert-butyl-D-alanyl-3-tert-butyl-L-alanine methyl ester (Example 8A, 36 g, 93.1 mmol) is dissolved in tetrahydrofuran p.a. (279 ml). At about 10° C., a solution of lithium hydroxide monohydrate (7.82 g, 186.3 mmol, 2 equivalents) in water (187 ml) is slowly added dropwise. When the HPLC chromatogram (Method 2) shows complete conversion (about 20 h), the reaction mixture is freed of the THF at 200 mbar and then extracted with methyl tert-butyl ether (200 ml). The organic phase is diluted with ethyl acetate (500 ml) and then water is added and the mixture is subsequently adjusted cautiously to pH 3-4 with 1 N aqueous hydrochloric acid. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, evaporated in vacuo and dried under high vacuum. 97.4 g (97% of theory) of the title compound are added.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: CCOC(=O)Cc1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2cn3cccnc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A mixture of 6 g of ethyl 4-(imidazo[1,2-a]pyrimidin-2-yl)phenyl-acetate, 30 ml of ethanol, 1.1 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The crystalline precipitate is filtered off, washed with ethanol, and then dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 3.2 g of 4-(imidazo-[1,2-a]pyrimidin-2-yl)phenylacetic acid as colorless crystals melting at 264°-265°C with decomposition.