Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:32]([CH3:33])[CH:29]1[CH2:30][CH2:31][N:26]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:51]([C:48]4[C:49](=[O:50])[N:44]([C:41]5[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=5)[N:45]=[CH:46][CH:47]=4)=[O:52])=[CH:20][C:19]=3[F:25])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[N:9]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (25.63 mg, 0.1095 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.95 mg, 0.3649 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol), N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39]1(=O)[CH2:42][CH2:41][CH2:40]1>>[CH2:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([CH:39]4[CH2:42][CH2:41][CH2:40]4)[CH2:9][CH2:10]2)=[O:16])=[CH:25][CH:24]=3)=[O:27])[CH2:33][CH2:32]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1
Reactant: O=C1CCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C5CCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47, from 4-[2-(4-ethoxycarbonyl-piperazine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester and cyclobutanone. Light-yellow solid. MS (m/z): 482.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([CH3:28])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:28])[CH:20]=1
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc4ccccc4cc23)c(C)cc1Cl
Yield: 71 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 102.9 mg (0.60 mmol) of 4-chloro-5-methoxy-2-methylaniline (can be prepared by the procedure disclosed in WO 85/01939, which is hereby incorporated by reference) and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 130–135° C. for 1.5 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 159.3 mg (72.2%) of the pure product as a yellow solid, mp 195–197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH:19]=[N:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:4]=1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(OCCCN2CCOCC2)c(CNCCc2ccccc2)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A stirred solution of 4-[3-[4-methoxy-2-[[(2-phenylethyl)imino]methyl]phenoxy]propyl]morpholine (41.7 g) in 190 ml of methanol is reduced with 12.4 g of sodium borohydride (added portionwise). A cold water bath is used to maintain the temperature of the reaction mixture at 35° C. After 3 hours, the solvent is treated with water and the product is extracted two times with ether. The ether fractions are combined, treated with water, dried and concentrated to give 33.3 g of the title compound, boiling point 249°-254° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:9](=[O:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3,3 diphenylpropionic acid (1.45 g, 6.44 mmol) in dry CH2Cl2 (70 ml) was added mono-boc piperizine (1.32 g, 7.08 mmol) under nitrogen. To the reaction was added EDC (2.71 g, 14.16 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (200 ml). The organic was washed with water (50 ml, 2×) and 10% NaOH (50 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (1:1) to give desired product in 76% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]([OH:17])[CH2:13][CH2:14][CH2:15]O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]3[CH2:13][CH2:14][CH2:15][O:17]3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(O)CCCO)oc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cccc2cc(C3CCCO3)oc12
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 1-(7-methoxybenzofuran-2-yl)-butane-1,4-diol (0.88 g) was treated with p-toluenesulfonic acid monohydrate (10 mg) and 3 Å molecular sieves in dichloromethane (10 ml) at ambient temperature. After stirring for 1 hour the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluting with 20% ethyl acetate in hexane to give the title compound as a yellow oil (0.58 g).
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:20][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:12][C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2]1
Reactant: CC(=O)c1ccccc1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2ccccc2)OCC(C(=O)c2ccccc2)(c2ccccc2)O1
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 12.1 grams (50 millimoles) of α-methylol benzoin, 6.0 grams (50 millimoles) of acetophenone, 1.0 gram of p-toluenesulfonic acid and 100 ml. of benzene was refluxed under a Dean-Stark trap for 2 hours, the mixture allowed to stand overnight at room temperature, then saturated with ammonia gas and filtered. The resulting oil was distilled at 135°-165° C at 20μ vacuum pressure to yield 10.5 grams of an only partially pure product. 7.2 grams of this product were chromatographed on silica gel with 5% diethyl ether-hexane elution to yield 6.2 grams of a product that was still not entirely pure, which was subjected to NMR and infrared examination as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1
Reactant: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
In a round bottom flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (118 mg, 0.23 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (9 mg). The mixture was stirred at 25° C. for 16 h and then concentrated in vacuo, dissolved in ethyl acetate with a little methanol to solubilize the material and concentrated in vacuo with silica gel (1 g). Purification by Biotage flash chromatography (AnaLogix, 12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (80 mg, 74%) as a white foam: HR-ES-MS m/z calculated for C21H25N4O5ClS [M+H]+ 481.1307, observed 491.1307; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.96-2.19 (m, 2H), 2.09 (s, 3H), 2.29-2.48 (m, 2H), 3.21-3.33 (m, 2H), 3.69-3.81 (m, 1H), 3.86 (dd, J=13.5, 7.5 Hz, 1H), 4.09 (dd, J=13.5, 3.8 Hz, 1H), 4.27 (d, J=18.2 Hz, 1H), 4.56 (d, J=18.2 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.78-4.86 (m, 1H), 4.81 (s, 1H), 4.94 (d, J=5.4 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.37 (td, J=7.8, 1.8 Hz, 1H), 7.47 (td, J=7.8, 1.4 Hz, 1H), 7.50-7.55 (m, 2H), 7.66 (dd, J=7.8, 1.4 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1>>[NH:35]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:37]=[N:36]1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4cn[nH]c4)nc3s2)cc1
Yield: 37 %

Procedure:
The titled compound (yield=37%) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.48 (s, 3H) 7.57 (d, J=8.34 Hz, 2H) 7.83 (d, J=8.59 Hz, 1H) 8.02-8.17 (m, 3H) 8.28 (s, 2H) 12.88 (s, 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.CS(O)(=O)=O>ClC1C=CC=CC=1>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[S:30][C:14]3[CH:15]=[C:16]([O:17][CH3:18])[CH:19]=[CH:20][C:13]=3[CH:11]=2)=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Temperature: 100 °C
Yield: 10 %

Procedure:
Anisoin (2.87 g), 50 ml of chlorobenzene, and Lawesson's Reagent 4.04 g are placed in a flask under nitrogen. The mixture is heated to 100° C. and a methanesulfonic acid (0.65 mL) is added and the mixture heated at reflux for 92 hours. The reaction is cooled to room temperature before filtering the solids which form. The filter cake is washed with 25 ml of chlorobenzene and dried to give 270 mg of product. The solid is recrystallized from hot chlorobenzene to give 90 mgs of pure product. Analysis calculated for C16H14O4S: C, 71.08; H, 5.22; S, 11.86. Found: C, 71.27; H, 5.43; S, 11.78. MS.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC([C:32]3[CH:37]=[CH:36][C:35](F)=[CH:34][C:33]=3[C:39]3[CH:40]=[N:41]C=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]4[C:33]=3[CH:39]=[CH:40][NH:41]4)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1cccc3[nH]ccc13)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one using 4-boronic acid-1H-indole instead of 3-pyridyl boronic acid.
Reaction SMILES: [CH3:1][CH:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCNC1
Yield: 96.7 %

Procedure:
A solution of 23.1 g (61.6 mmol) of [1-methyl-2-[[(3-methyl-1-(phenylmethyl)-3-pyrrolidinyl)methyl]-amino]-2-oxoethyl]carbamic acid, 1,1-dimethylethyl ester in 400 ml of methanol was treated with 3.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at temperatures of 22°-26° and pressures of 48.7-53.4 psi for 2.5 hours. The catalyst was removed by filtering through celite and the filtrate was evaporated in vacuo to give 17.0 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[S:17])[S:8][S:9][C:10]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:5])C>C(O)(=O)C.S(=O)(=O)(O)O.O>[C:4]([C:6]1[C:7](=[S:17])[S:8][S:9][C:10]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2cnccn2)ssc1=S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(-c2cnccn2)ssc1=S
Temperature: 20 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
A solution of 4-ethoxycarbonyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (150 g) [prepared as described in Example 31] in acetic acid (6750 cc), concentrated sulphuric acid (515 cc) and water (515 cc) is heated for 2 hours under reflux. After cooling, the product which crystallises is filtered off and washed successively with acetic acid (100 cc) and carbon disulphide (2 × 100 cc). This product is then suspended in water (1350 cc) and stirred for 48 hours at a temperature of about 20° C. The insoluble product is then filtered off and washed with water (2 × 250 cc). After drying, 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (97.5 g), melting at 225° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:29])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=2[CH:28]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:30][O:31][C:32]([C:34]1[C:35]([Cl:41])=[N:36][C:37](Cl)=[CH:38][CH:39]=1)=[O:33].C1N2CCN(CC2)C1>>[CH3:30][O:31][C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:29])[C:10]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=4[CH:28]=3)([OH:15])[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:36][C:35]=1[Cl:41]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)cc21
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: C1CN2CCN1CC2
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(Oc4ccc(C(=O)OC)c(Cl)n4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 62 step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (Example 64, step 5) was reacted with methyl-2,6-dichloro-pyridine-3-carboxylate and DABCO (21 h, r.t.) to give the title compound as a white solid. MS (m/e)=599.3 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28]C1C=CC(CC=O)=CC=1>C(Cl)Cl.CO>[CH3:27][O:28][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Reactant: COc1ccc(CC=O)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (4-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 396.0 [M+H]+; single peak at tR=6.36 min (System 1); R4=0.28 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5](O)[C:4]=2[CH:3]=1.[O:17]=[C:18]([CH:25]1[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[O:30])[CH2:26]1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C.C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([CH:19]([C:18](=[O:17])[CH:25]3[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:34])=[O:30])[CH2:26]3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]=2[CH:3]=1
Reactant: OC1c2ccccc2Sc2ccc(Cl)cc21
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1)C1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 60 °C

Procedure:
2-Chloro-9-hydroxythioxanthene (0.72 g, 2.89 mmol) was allowed to react with ethyl 3-oxo-3-(3-phenacyloxycarbonylcyclobutyl)propanoate (0.8 g, 2.41 mmol) in acetic acid (4 ml) and ethanol (4 ml) for 4 days and then heated at 60° C. for 4 hours. Worked up following procedure described in Example 6(i) to give a yellow oil. The crude product was purified by chromatography on flash silica eluting with chloroform then chloroform-methanol (99.5:0.5 then 99:1) to give the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([N:16]1[CH2:19][C:18]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:17]1)[CH2:11][CH2:10]2.[ClH:32].CO>O1CCOCC1>[ClH:32].[ClH:32].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([N:16]1[CH2:17][C:18]3([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH2:19]1)[CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ncccn4)ccc31)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cnc(-c2ccc3c(c2)CC[C@@H]3N2CC3(CCNCC3)C2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a round-bottomed flask containing tert-butyl 2-[(1R)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1d, 177 mg, 0.42 mmol) was added 5 mL of 4N HCl in dioxane. The mixture was stirred for 3 hours at room temperature and 2 mL of methanol was added to solubilize the reaction. After stirring an additional hour, the volatiles were removed under reduced pressure to give the title compound as a brown solid (190 mg, 100%). MS (APCI) 321.4 (M+H)+. 1H NMR (CD3OD) δ 2.14-2.22 (m, 5H), 2.58 (br s, 1H), 3.11 (d, 1H), 3.19-3.23 (m, 5H), 4.12 (d, 1H), 4.21 (s, 2H), 4.45-4.47 (m, 1H), 5.07-5.08 (m, 1H), 7.51 (t, 1H), 7.74 (s, 1H), 8.34-8.40 (m, 2H), 8.94 (d, 2H).
Reaction SMILES: BrC([CH:7](Br)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15])CC(O)=O.CC(C)([O-])C.[K+].Cl.[C:24]([O:27]CC)(=[O:26])[CH3:25]>C(O)(C)(C)C>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:7]#[C:25][C:24]([OH:27])=[O:26]
Reactant: O=C(O)CC(Br)C(Br)c1ccc(Cl)cc1Cl
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reaction time: 1.5 h

Procedure:
A solution of 19.2 g (50.94 mmol) of 2,3-dibromo-3-(2,4-dichlorophenyl)propanecarboxylic acid in 130 mL of tert-butanol is combined batchwise with a total of 22.86 (203.78 mmol) of potassium tert-butoxide, so that the temperature does not exceed 40° C. Then the mixture is stirred for another 90 minutes at this temperature. The reaction mixture is poured into 2N hydrochloric acid and the precipitate is taken up in ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the solvent is distilled off. The residue is dried in the circulating air dryer at 80° C. Yield: 9.73 g (88.8% of theory); melting point: 168° C.-171° C.; C9H4Cl2O2 (M=215.03); Rf value: 0.5 (silica gel, dichloromethane/ethanol/glacial acetic acid (10:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 48.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.034 g (48%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide as a white solid.