Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Yield: 9 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethoxy)aniline (62.8 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 9.5 mg (32 μmol; 9% yield) of pure desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:5][Mg]Cl.C(OCC)C.CN(CCN(C)C)C.[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])/[CH:34]=[N:35]/[S@:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1>[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[C@@H:34]([NH:35][S@:36]([C:38]([CH3:39])([CH3:40])[CH3:41])=[O:37])[CH2:5][C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A 500 mL RB flask containing (3-chloro-5-fluorobenzyl)magnesium chloride, 0.25 M in diethyl ether (13040 μl, 3260 μmol) was allowed to stir at −78° C. for 5 minutes. At this time, TMEDA (492 μl, 3260 μmol) was added via a syringe and then THF (10 mL) was added via a syringe and the mixture was allowed to stir for 15 min before the addition of (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (550.00 mg, 1304 μmol) (14 mL THF) via a syringe. The reaction was allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100 mL). The aq. layer was extracted with EtOAc (3×100 mL). The combined organics were washed with brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give 1.30 g of a crude oil that was purified on a 120 g ISCO column to give the title compound. Rf=0.40 in 20% EtOAc in hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl.[OH-].[Na+].CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 8-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane (0.97 g, 2.36 mmol) in 1,4-dioxane (16 mL) was slowly added concentrated HCl (24 mL) and the resulting solution was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and the pH was adjusted to 12 by careful addition of an aqueous solution of NaOH (50% w/v). EtOAc was added, the layers were separated and the aqueous layer was extracted further with EtOAc. The combined organic layers were dried (Na2SO4), then concentrated in vacuo to give the title compound as a yellow solid (0.9 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].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>>[F:29][C:30]([F:34])([F:33])[CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCC(F)(F)F
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(F)(F)F)ccc21
Yield: 85.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (102 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2,2,2-trifluoroethylamine (27 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 490.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 9.05 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 4.18-4.01 (m, 2H), 3.62 (bs, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetylamino-phenylboronic acid to give N-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-phenyl}-acetamide. LC-MS m/e 388(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[B:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)([OH:30])[OH:26]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanoic acid (15 g, 61.7 mmol) in anhydrous THF (150 mL) was added at −78° C. under argon a 2.5 M solution of n-butyllithium in hexane (37 ml, 92.6 mmol) dropwise, followed by triisopropyl borate (43 ml, 185.1 mmol). After the addition, the reaction mixture was stirred at −50° C. for 2 hrs and allowed to warm up to room temperature and stirred over night. The reaction mixture was quenched with 1 N HCl then extracted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 13 g of product as a white solid in 99% yield. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 6H), 7.25-7.27 (d, 2H), 7.29-7.47 (dd, 1H), 7.68-7.70 (d, 1H), 12.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO>[F:12][C:10]1[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:11]=1
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2cc(Br)cc(F)c21
Agent: [K+]
Solvent: CCO
Product: C=Cc1cc(F)c2c(c1)COC2=O

Procedure:
A mixture of 5-bromo-7-fluoro-2-benzofuran-1(3H)-one (4.6 g, 20.0 mmol), potassium vinyltrifluoroborate (2.9 g, 22 mmol) and Pd (dppf)2Cl2 (0.5 g) in 40 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. After concentration, the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.23 (s, 1H), 7.17 (d, J=10.0 Hz, 1H), 6.70-6.77 (m, 1H), 5.89 (d, J=17.2 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H), 5.28 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:27]3[CH2:28][O:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: Cc1cc(-c2n[nH]c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reaction time: 72 h
Yield: 56.1 %

Procedure:
To a solution of 3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 mL, 526 mmol) in DMF (100 mL) was added cesium carbonate (20.56 g, 63 mmol). The reaction mixture was allowed to stir for 72 h, diluted with EtOAc (200 mL) and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to afford 3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (12.0 g, 57%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.68. MS (electrospray) m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3) 7.55 (s, 1H), 7.36 (m, 2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H), 4.11 (dd, J=14.3, 5.7 Hz, 1H), 3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J=4.5 Hz, 1H), 2.75 (m, 2H), 2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[C@@H:15]([NH:22]C(=O)OC(C)(C)C)[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:22][C@@H:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14]([NH:13][CH2:12][CH2:11][NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)NCCNc1nc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccs1)C(=O)NCCNc1nc2ccccc2s1
Reaction time: 4 h

Procedure:
(S)-tert-butyl 1-(2-(benzo[d]thiazol-2-ylamino)ethylamino)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (195.9 mg, 0.439 mmol) was suspended in 1,4-dioxane (4 mL) and treated with 4N HCl in 1,4-dioxane (4 mL, 16.0 mmol). The resulting mixture became homogenous, then a solid separated as the stirring continued for 4 h. The solid was collected by filtration, washed with 1,4-dioxane, then dried in a vacuum oven overnight at room temperature, to yield the title compound as its corresponding hydrochloride salt, as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([OH:19])=[O:18].CC(O)=O>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(C(=O)O)cc3)nc12

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-carboxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 50-100% [5% AcOH:EtOAc]/Hexanes as eluant gave 10 mg (6%) of a pale brown solid. M+H=324.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][N:38]([CH2:37][CH:34]6[CH2:36][CH2:35]6)[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:32])([F:31])[F:33])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Reactant: C1CN(CC2CC2)CCN1
Product: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(CC5CC5)CC4)=NC3=O)cc12

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrile was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 1-Cyclopropylmethyl-piperazine following General Procedure C.
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([O-:16])=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:3])[CH3:2].[Li+].Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:7]4[O:6][C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:17])=[N:9][C:8]=34)=[O:16])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CC(C)N(C)c1nc2c(C(=O)[O-])cccc2o1
Agent: Cl
Agent: [Li+]
Product: CC(C)N(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of lithium 2-(isopropyl(methyl)amino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to afford (S)—N-(quinuclidine-8-yl)-2-(isopropyl(methyl)amino)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][C:9]=1[F:23])=[O:6].[OH-].[NH4+:26]>>[F:23][C:9]1[CH:10]=[C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Yield: 87 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=87%. Slightly yellow solid. MS: m/e=321.3 (M++H).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:26][C:27]([CH3:34])([C:30]([F:33])([F:32])[F:31])[C:28]=1[CH3:29])#[N:23]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([CH3:34])([C:30]([F:33])([F:31])[F:32])[O:26][C:25](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 92.3 %

Procedure:
In 5 ml of ethanol were dissolved 145 mg (0.50 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 140 mg (0.55 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 242 mg of a dark greenish brown crystal (yield: 92.1%; mp: 169-170° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 194 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=92-93° C., 400 MHz 1H NMR (CDCl3) δ: 8.00-7.97 (d, J=8.21 Hz, 1H), 7.668-7.663 (d, J=1.95 Hz, 1H), 7.46-7.43 (dd, J=1.95, 8.21 Hz, 1H), 7.33-7.23 (m, 5H), 4.09-3.94 (m, 1H), 3.33 (br s, 1H), 2.88-2.82 (m, 4H), 2.75-2.70 (m, 3H), 2.52-2.41 (m, 3H), 2.14-2.11 (d, J=12.9 Hz, 2H), 1.94-1.80 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]([CH3:11])=[O:10])=[CH:5]OCC)=[O:3].[NH2:12][C:13]1[C:14]([Cl:23])=[C:15]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17]>CCOCC>[CH3:11][C:9]([C:4]([C:2]([CH3:1])=[O:3])=[CH:5][NH:12][C:13]1[C:14]([Cl:23])=[C:15]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:10]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: CCOC=C(C(C)=O)C(C)=O
Solvent: CCOCC
Product: CC(=O)C(=CNc1cc(Cl)cc(C(=O)O)c1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
9.35 g (0.06 mole) of methyl 1-methylcarbonyl-2-ethoxyvinyl ketone were added dropwise to a suspension of 10.3 g (0.05 mole) of 3-amino-2,5-dichlorobenzoic acid in 40 ml of ether. The mixture was stirred for a further 5 hours at room temperature and the precipitate was then filtered off and washed with acetonitrile. 12 g (76% of theory) of 3-[2,2-bis-(methylcarbonyl)-vinylamino]-2,5-dichlorobenzoic acid were obtained in the form of colourless crystals of melting point 244°-246° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Na].S(=O)(=O)=O>CC(N(C)C)=O.O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([C:17]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S(=O)=O
Agent: [Na]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-aminobenzamide (1.36 g, 9.99 mmol, 1.00 equiv) in dimethylacetamide (25 mL), 4-(dimethylamino)benzaldehyde (1.49 g, 9.99 mmol, 1.00 equiv) and sulfonylideneoxidane sodium (1.6 g, 15.53 mmol, 1.50 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 100 mL of water. The solids were collected by filtration. The solid was washed with 2×20 mL of water and 1×20 mL of petroleum ether. This resulted in 2.1 g (79%) of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Br)cc1

Procedure:
To 4.9 grams (0.05 mole) of 2-imino-1-methylpyrrolidine in anhydrous benzene is added, dropwise with stirring, 9.9 g. (0.05 mole) of p-bromophenylisocyanate dissolved in anhydrous benzene. Solid material forms as the reaction mixture is stirred at room temperature overnight. This solid, 1-p-bromophenyl-3-(1-methyl-2-pyrrolidylidene)urea, is collected, (m.p. = 135°-137° C). A second cup (m.p. = 134°-136° C) is also obtained from the mother liquor. The two crops are combined and recrystallized from isopropanol-ether to give pure 1-p-bromophenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 136°-138° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:11].CS[C:14]1[NH:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(#N)C>[IH:11].[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][NH:23][C:14]=1[NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1ccccc1
Reactant: CSC1=Nc2ccccc2CN1
Agent: I
Solvent: CC#N
Product: c1ccc(OCCNC2=Nc3ccccc3CN2)cc1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
2-Phenoxyethylamine (21 mg, 0.16 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.16 mmol, prepared as under example 1 [c]) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The solvent was then evaporated and the mixture was suspended in diethyl ether. The title compound (41 mg, 95%) was obtained from this mixture by filtration.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Product: Cc1sc2cc3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C

Procedure:
Using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol and 4-chlorosulphonyl-2-hydroxybenzoic acid the title compound was prepared according to the procedure in Example 1, step 9. Purification on 2% H3PO4 /MeOH treated silica gel eluting with a 0 & 10% EtOAc/hexane step gradient gave 0.66 g of the title compound as a pale yellow solid, mp 230-237° C.; 1H NMR (DMSO-d6) δ 1.30-1.35 (m, 2 H), 1.45-1.52 (m, 5 H), 1.58-1.63 (m, 3 H), 2.40 (s, 2 H), 3.05 (q, 1 H), 7.21-7.29 (m, 4 H), 7.35-7.47 (m, 4 H), 7.97 (d, 1 H), 8.03 (d, 1 H), 8.49 (s, 1 H). IR (KBr) 2950, 1675, 1390, 1190 and 850 cm-1. mass spectrum (-ESI), m/z 571 (M-H). Anal. Calcd. for C32H28O6S2.0.2H2O: C, 66.69; H, 4.97 N, 0.00. Found: C, 66.69; H, 5.01 N, 0.03.