Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.BrN1C(=[O:16])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)(Cl)Cl.O>[OH:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
The compound of Example 1A (13 g, 110 mmol) is dissolved in 400 ml tetrachloromethane, and 29.4 g (165 mmol) N-bromosuccinimide and 0.4 g (1.6 mmol) dibenzoylperoxide are added. The reaction mixture is refluxed for three hours, cooled down to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is dissolved in 200 ml dioxane and 200 ml water, calcium carbonate (44 g, 440 mmol) is added, and the mixture is stirred at reflux for 2 hours. After cooling down to room temperature, the mixture is filtered, and dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent: cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-methyl-piperazine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H37N6O2Cl2 [(M+H)+] 595.2350, observed 595.2351.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13](O)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)([Cl:24])=O.[C:27]([O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)(=[O:30])[NH:28][NH2:29]>O>[CH:35]1[C:34]2[CH:33]([CH2:32][O:31][C:27]([NH:28][NH:29][C:13]([C:6]3[C:7]([Cl:24])=[N:8][C:9]4[C:4]([C:5]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=4)=[O:14])=[O:30])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Product: O=C(NNC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1)OCC1c2ccccc2-c2ccccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (100 mg, 334 μmol, Eq: 1.00) and phosphorus oxychloride (3.29 g, 2 ml, 21.5 mmol, Eq: 64.3) was heated to 120° C. for 3 h. The reaction mixture was evaporated to dryness and the remaining residue was co-evaporated with toluene (2×). The residue was dissolved in DCM (1 ml) and 9-fluorenylmethyl carbazate (127 mg, 500 μmol, Eq: 1.5) was added. The reaction mixture was stirred at RT for 4 h. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 9:1) to afford the title compound as off-white solid (102 mg). MS (ESI): 554.1 (M+H)+.
Reaction SMILES: NCCC1C=CC(NC(C2C=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=CC=2)=O)=CC=1.[C:45]([C:48]1[CH:49]=[N:50][C:51]2[C:56]([C:57]=1[NH:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=1)=[CH:55][C:54]([S:67]([C:70]1[CH:71]=[C:72]([CH:96]=[CH:97][CH:98]=1)[C:73]([N:75]([CH2:77][CH2:78][O:79][C:80]1[CH:95]=[CH:94][C:83]([CH2:84][CH2:85][NH:86]C(=O)OC(C)(C)C)=[CH:82][CH:81]=1)[CH3:76])=[O:74])(=[O:69])=[O:68])=[CH:53][C:52]=2[CH3:99])(=[O:47])[NH2:46]>>[NH2:86][CH2:85][CH2:84][C:83]1[CH:94]=[CH:95][C:80]([O:79][CH2:78][CH2:77][N:75]([CH3:76])[C:73]([C:72]2[CH:71]=[C:70]([S:67]([C:54]3[CH:55]=[C:56]4[C:51](=[C:52]([CH3:99])[CH:53]=3)[N:50]=[CH:49][C:48]([C:45]([NH2:46])=[O:47])=[C:57]4[NH:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=3)(=[O:68])=[O:69])[CH:98]=[CH:97][CH:96]=2)=[O:74])=[CH:81][CH:82]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCNC(=O)OC(C)(C)C)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCN)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCN)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 94, using Intermediate 83 as a substrate. ES/MS calcd for C36H38N5O6S+ 668.25. Found m/z=668.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Solvent: c1ccncc1
Product: Cc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 573 mg, 3.06 mmol) in pyridine (6 ml) was added dropwise methanesulfonyl chloride (Aldrich, Buchs, Switzerland, 0.286 ml, 3.68 mmol). The reaction mixture was stirred for 18 h at rt then are added methanesulfonyl chloride (0.03 ml, 0.39 mmol). The reaction mixture was stirred 4 h at rt before being evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-5%) to give the title compound as a pinkish solid. (HPLC: tR 2.05 min (Method A); M+H=265, 267 MS-ES).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19](O)=[O:20])[NH:10]1.[ClH:22]>CCOCC>[ClH:22].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])[NH:10]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1Cc2ccccc2CN1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Benzyl alcohol, 750 ml, was treated with 150 g of commercial polyphosphoric acid and warmed and stirred at 90° C. to obtain a homogeneous mixture. Solid 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S-form) 165.2 g was added. The mixture was stirred 4 hours at 95°-105° C. and then allowed to stand at room temperature for 18 hours. A solution of 18.5 g gaseous hydrochloric acid in 2.5 l of anhydrous ether was added, and the product separated slowly on cooling overnight. Filtration gave the crude benzyl 1,2,3,4-tetrahydro-3-isoquinoline carboxylate hydrochloride. This was purified by recrystallization from ethanol twice to give material with mp 190.5°-191° C.; [α]D 23=-83.3° (1% 1:1 methanol/1 N hydrochloric acid).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([S:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([OH:26])(C)C>O>[F:22][C:11]([F:10])([F:21])[C:12]1[CH:13]=[C:14]([S:18]([C:2]2[CH:7]=[CH:6][C:5](=[O:26])[NH:4][N:3]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S([O-])c1cccc(C(F)(F)F)c1
Reactant: CC(C)O
Reactant: Clc1ccc(Cl)nn1
Agent: [Na+]
Solvent: O
Product: O=c1ccc(S(=O)(=O)c2cccc(C(F)(F)F)c2)n[nH]1
Yield: 25 %

Procedure:
A mixture of 3,6-dichloropyridazine (4.44 g), 3-trifluoromethylphenyl sulfinic acid sodium salt (6.93 g), isopropanol (30 mL), and water (1 mL) was prepared and refluxed for 18 hours. The reaction mixture was then cooled, diluted with water (100 mL) and the precipitated solid was collected. The solid was triturated with n-propanol and the solid was collected to obtain the title compound (25%, 2.3 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH2:18])#[N:2].[N+:19]([C:22]1[CH:32]=[CH:31][C:25](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20].CN1[C:38](=[O:39])CCC1>>[NH2:18][C:7]1[C:6]([S:5][CH2:4][CH2:3][C:1]#[N:2])=[CH:11][C:10]([N:12]([C:28](=[O:29])/[CH:27]=[CH:26]/[C:25]2[CH:31]=[CH:32][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:38]=[O:39])=[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])[CH:8]=1
Reactant: N#CCCSc1cc(N)c(SCCC#N)cc1N
Reactant: O=C(Cl)/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCC1=O
Product: N#CCCSc1cc(N(C=O)C(=O)/C=C/c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1N
Temperature: 0 °C
Yield: 78.13 %

Procedure:
2,5-Bis[(cyanoethyl)thio]-1,4-phenylenediamine (2.50 g, 9.00 mmol) was admixed with 15 mL of NMP in a 250 mL 3-necked round-bottom flask with nitrogen purge. The resultant mixture was cooled to around 0° C. in an ice bath with stirring, followed by the addition of trans-4-nitrocinnamoyl chloride (2.00 g, 9.45 mmol, dissolved in 13 mL NMP) drop by drop. Thereafter, the ice bath was removed, and 400 mL of water was poured into the flask to result in the formation of a solid precipitate, which was collected by filtration. The thus-obtained solid was added into 400 mL of water and heated to 60° C. for 10 min. After filtration, the collected solid was admixed with 600 mL of methanol, followed by filtration. An orange solid was obtained and dried in a vacuum oven at 80° C., giving the title compound in a yield of 78.13%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(F)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)cc(NS(C)(=O)=O)c3)n(-c3ccccc3)c(=O)c12
Yield: 57.3 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mmol) was treated with N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (34 mg, 0.11 mmol, prepared as described at WO 2004052847 A2 20040624), cesium carbonate (2M, 110 μl, 0.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) according to the method described in Example 3 to give 22 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>O1CCOCC1.O>[CH2:18]([O:25][C:7]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]#[N:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 200 mg (0.813 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2 ml dioxane under argon at 0° C., was added 425.3 ul (4.065 mmol) benzyl alcohol, followed by a dropwise addition of a solution of 82.2 mg (1.260 mmol) potassium hydroxide in 600 ul water. The mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice water. The resulting suspension was filtered and dried in vacuo to provide 196 mg (y: 78.5%) of the title compound as a white solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]([O-:7])([O-])=O.[K+].[K+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.O>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:7][CH3:4])=[CH:13][CH:14]=2)[C:2]#[N:3])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: N#CN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C#N)Cc2ccc(OC)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 1 g of cyanamide in 50 ml of DMF is admixed with 13.1 g of K2CO3 and 6.5 ml of 4-methoxybenzyl chloride and then heated at 80° C. for 20 hours. After cooling to AT, the reaction mixture is poured into water, and extracted with AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with an AcOEt/cyclohexane mixture (75/25; v/v). This gives 6.5 g of the expected compound in the form of an oil.
Reaction SMILES: [C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>CC(O)C>[C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)N(c2ccc(OC)cc2)C3)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.40 mmol) (from Example 19a supra) and p-anisidine (63.6 mg, 0.52 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 10 minutes. After cooling, it was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.14 g, 58%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][NH:39][CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.Cl>CN(C=O)C.C(OCC)(=O)C.O>[ClH:1].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][N:39]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCN(C)Cc2ccc(NC(=O)/C=C/c3cccc(-c4ccc(C)cc4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 2—(3,4-dimethoxyphenyl)ethylmethylamine (132 μl) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 12 hours, and to. the mixture was added water (50 ml). The mixture was extracted with ethyl. acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give colorless amorphous, which was dissolved in ethyl acetate (50 ml), and to the mixture was added 4N hydrochloric acid ethyl acetate solution (0.5 ml). The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give (E)-N-[4-[N-[2—(3,4-dimethoxyphenyl)ethyl]-N-methylaminomethyl]phenyl]-3—(4-methylphenyl)cinnamamide hydrochloride (Compound 63) (245 mg) as colorless crystals.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH:15]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[C:24]([O:32][CH3:33])[CH:23]=3)C(OCC)=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>CS(C)=O.O>[CH:1]1[C:14]2[CH:13]([CH2:15][C:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:34])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C(=O)OC)c(OC)c1)C1c2ccccc2Oc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)CC2c3ccccc3Oc3ccccc32)cc1OC

Procedure:
To a solution of ethyl 2-(9H-xanthen-9-yl)-2-(3-methoxy-4-methoxycarbonylbenzoyl)acetate (7.0 g, 14.6 mmol) in dimethylsulphoxide (40 ml) was added water (0.53 ml, 29.3 mmol). The solution was stirred under an atmosphere of nitrogen at reflux for 1.5 h before cooling and diluting with water. The mixture was extracted with dichloromethane (3×) and the combined extracts washed with water (5×) and a saturated solution of sodium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to a yellow oil. Purification on flash silica eluting with dichloromethane-hexane (3:2 then 4:1) gave a solid which was crystallised from methanol to give methyl 4-[2-(9H-xanthen-9-yl)acetyl]-2-methoxybenzoate as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH2:18][CH:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:14][C:13]2=[O:29])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:51][C:52]1[CH:56]=[CH:55][N:54]([CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[N:53]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH2:18][CH:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:14][C:13]2=[O:29])[C:9]([NH:51][C:52]2[CH:56]=[CH:55][N:54]([CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[N:53]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(OCC2COc3ccccc3O2)=CC1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(OCC3COc4ccccc4O3)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (151 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (63 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.38 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 67 mg, 0.43 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamide (47 mg, 24%) as a white solid: HR-ES-MS m/z calculated for C29H38N4O6 [M+H]+ 539.2864, observed 539.2865; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.99 (m, 2H) 1.05 (s, 3H) 1.07-1.30 (m, 4H) 1.50-1.83 (m, 7H) 3.89 (s, 2H) 3.98 (dd, J=18.1, 4.0 Hz, 1H) 4.09 (dd, J=11.3, 7.5 Hz, 1H) 4.18-4.34 (m, 2H) 4.34-4.45 (m, 1H) 4.53-4.63 (m, 1H) 4.67 (s, 1H) 4.86 (dd, J=11.3, 4.0 Hz, 1H) 5.25 (s, 1H) 6.42 (d, J=2.1 Hz, 1H) 6.79-6.99 (m, 4H) 7.52 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:20])[CH3:19].CC([O-])(C)C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:28][CH:27]=3)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3′,4′-dichloro-4-fluorobiphenyl-3-carbonitrile (173 mg, 0.650 mmol), 4-isopropoxyaniline (108 mg, 0.715 mmol), and KOtBu (154 mg, 1.375 mmol) in DMSO (4 mL) was stirred at rt for 1.5 h, The mixture was diluted with ethyl acetate, washed with H2O and brine, and then dried over Na2SO4. The solvent was removed and the product was purified by silica gel chromatography (eluting with hexane containing 0 to 8% ethyl acetate) followed by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=50:50 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min). This afforded 99 mg of 3′,4′-dichloro-4-(4-isopropoxyphenylamino)-biphenyl-3-carbonitrile which still contained some impurities according to the LC/MS but was used as such for next step. MS (ESI) m/z 397.1 (M+H).