Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[N:54]=[C:53]([CH2:55]Br)[CH:52]=[CH:51][C:49]=2[N:50]=1>>[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[N:54]=[C:53]([CH2:55][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[NH:39][C:40]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[S:32]4)[CH:52]=[CH:51][C:49]=2[N:50]=1
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(Cc3cccc4c3Nc3ccccc3S4)ccc2n1

Procedure:
9-[(2,4-Diaminopyrido[3,2-d]pyrimidin-6-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminopyrido[3,2-d]pyrimidin-6-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[3,2-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](O)=[O:11].S(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([Cl:16])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a mixture of the product from Example 4B (300 mg, 1.65 mmol) and thionyl chloride (901 μL, 12.4 mmol) was added a drop of dimethylformamide. The reaction was stirred at 22° C. for 2 hours. The excess of thionyl chloride was evaporated and the residue was dried under vacuum to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[C:14]([O:20]C)=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[C:14]([OH:20])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CCCc1cc(OC)c(C(=O)c2ccccc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(O)c(C(=O)c2ccccc2)cc1O
Temperature: -78 °C
Yield: 99 %

Procedure:
0.37 gram (1.3 mmole, 1.0 eq.) of product from step E was dissolved in 5 ml of dichloromethane. The solution was stirred under nitrogen atmosphere at -78° C. and 3.2 ml of 1.0 M boron tribromide solution in hexanes (3.2 mmole, 2.5 eq.) was added dropwise over a 5-8 minute span. The reaction was allowed to slowly warm, and after 3 hours ice was added to the reaction mixture. After an additional 30 minutes some water was added and the mixture was diluted with dichloromethane. The layers were separated and the organic was washed twice more with water, dried over sodium sulfate, filtered and evaporated to give the title compound (0.33 gram, 100% yield) without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH2:8][C:2]2=[O:1])=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN=C(c3ccccc3)c3ccccc32)cc1

Procedure:
A mixture of 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine (13.43 g, 57 mmmol, prepared as described by Mark G. Bock et al in Journal of Organic Chemistry, Vol. 52, pp. 3232-3239, year 1987), 4-methoxybenzyl chloride (12.6 mL, 62.5 mmol) and potassium carbonate (15.7 g, 114 mmol) in N,N-dimethylformamide (130 mL) was heated at 60° C. overnight under an atmosphere of argon. The resultant slurry was concentrated and the residue was treated with ethyl acetate and water. The organic extract was separated, washed twice with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuo. The residue was subjected to column chromatography on silica gel eluting with 1:1 ethyl acetate and hexane. Collection and concentration of appropriate fractions provided 2,3-dihydro-1-[4-methoxybenzyl]-2-oxo-5-phenyl-1H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:14]([CH3:36])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([NH:28][C:29]2[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:16]=3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[C:37](O)(=O)[CH3:38]>>[CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:14]([CH3:36])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N:35]=[C:37]2[CH3:38])[N:16]=3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C)CC1
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Yield: 21.1 %

Procedure:
A mixture of N1-(8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)benzene-1,2-diamine (177 mg, 0.368 mmol) in acetic acid (1.5 mL) was stirred at reflux for 5 hours. The reaction mixture was then concentrated and then purified first by flash chromatography (10% MeOH in DCM containing 1% 2 M ammonia in MeOH), followed by RP-HPLC to give 179 (0.0373 g, 21.1%). LCMS: M+H+=519.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2].CN(C)N.C>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(C)=O)c1
Agent: C
Agent: CN(C)N
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: (3-{2-[(acetyl-ethyl-amino)-methyl]-4-nitro-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester, 1,1-dimethylhydrazine, ferric chloride, and DARCO.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1)[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [OH:1][C@:2]([C:9]1[CH:14]=[CH:13][N:12]=[C:11](OC)[C:10]=1[CH2:17][OH:18])([CH2:7][CH3:8])[CH2:3][C:4](O)=O.Br>COCCOC>[CH2:7]([C@:2]1([OH:1])[C:9]2[CH:14]=[CH:13][NH:12][CH2:11][C:10]=2[CH2:17][O:18][CH2:4][CH2:3]1)[CH3:8]
Reactant: CC[C@@](O)(CC(=O)O)c1ccnc(OC)c1CO
Agent: Br
Solvent: COCCOC
Product: CC[C@@]1(O)CCOCC2=C1C=CNC2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1.097 g (R)-3-hydroxy-3-(3-hydroxymethyl-2-methoxy-pyridin-4-yl)-pentanoic acid (4.298 mmol) as obtainable from example 19, in 15.1 mL 1,2-dimethoxyethane, were added 1.014 mL aqueous HBr (48%) (9.03 mmol, 2.1 eq). After 15 min at room temperature, the solution was heated to 50° C. After 18 h at 50° C., the resulting suspension was allowed to stir at room temperature for additional 24 h and subsequently to stand at 5° C. for 18 h. The precipitate was collected by filtration using no vacuum and was subsequently washed twice with 2.55 mL, in total with 5.1 mL TBME, then with 2.55 mL acetone, two times with 3.18 mL, in total with 6.36 mL water and finally two times with 3.18 mL, in total with 6.36 mL acetone. After evaporation of residual solvent in a rotary evaporator (40° C./10 mbar), the title compound was obtained as white crystals (418.1 mg, 1.873 mmol, 44% w/w), in high purity (HPLC purity 100% area), and in an enantiomeric ratio of er=100.00:0.00 (see chiral HPLC method below).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:34]2[CH:39]=[CH:38][C:37](O)=[C:36]([CH3:41])[CH:35]=2)([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][C:24]=1[CH3:42].C(OCC)(=O)C>ClCCl>[CH2:30]([C:29]([C:34]1[CH:39]=[CH:38][C:37]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:36]([CH3:41])[CH:35]=1)([C:26]1[CH:27]=[CH:28][C:23]([OH:22])=[C:24]([CH3:42])[CH:25]=1)[CH2:32][CH3:33])[CH3:31]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(O)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Pyridine (3 mL, 37.2 mmol) and trifluoromethanesulfonic anhydride (5.7 mL, 34.7 mmol) were added to a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (9.0 g, 31.6 mmol) in dichloromethane (300 mL) at 0° C., and then the mixture was stirred at the same temperature for one hour. Ethyl acetate was added to the reaction mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=10/1 to ethyl acetate only) to give the title compound (4.9 g, 37%).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:19]2[N:26]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: O=C1Cc2cnc(-c3ccccc3)nc2-c2ccccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, them 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and benzamidine hydrochloride. Yield: 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)[CH2:18]C3C=CC=CC=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.C=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N(Cc3ccccc3)C3CCNC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: C=O
Product: Cc1ccc(NC(=O)c2ccc(N(C)C3CCNC3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The intermediate prepared from Example 5 that was N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}[4-(N-benzylpyrrolidin-3-ylamino)phenyl]-carboxamide was methylated via reductive amination with HCHO/NaBHCN (1.5 eq) and further hydrogenated to remove benzyl protection at 50 psi in EtOH catalized by Pd/C (10%) overnight to give the title compound. Mass: (M+1), 480.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[C:28]([F:29])=[C:27](F)[N:26]=[CH:25][N:24]=1>C(#N)C>[CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:27]1[C:28]([F:29])=[C:23]([F:22])[N:24]=[CH:25][N:26]=1)=[N:5][O:6][CH3:7]
Reactant: Fc1ncnc(F)c1F
Reactant: CNC(=O)C(=NOC)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (0.0280 mol) of N-methyl-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide (Example I-1g from process step 1; HPLC: 43.7% N-methyl-E-2-(2-hydroxyphenyl)-2-methoxyimino-acetamide of log p=0.98 and 53.5% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29) are dissolved in 80 ml of acetonitrile. The solution is cooled to 0° C., 4.7 g (0.034 mol) of potassium carbonate are added and the mixture is stirred for another 30 minutes. 3.8 g (0.0283 mol) of 4,5,6-trifluoropyrimidine are then added dropwise and the mixture is stirred at 20° C. for two hours. The solvent is then distilled off under reduced pressure, the residue is mixed with water, the product is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 5.7 g (61.4% of theory) of crude N-methyl-2-[2-(5,6-difluoropyrimidin-4-yloxy)phenyl]-2-methoxyiminoacetamide which, according to HPLC, contains 45.5% N-methyl-E-2-[2-(5,6-difluoropyrimidin-4-yloxy)-phenyl]-2-methoxyiminoacetamide of log p=1.95 and 46.6% N-methyl-Z-2-[2-(5,6-difluoro-pyrimidin-4-yloxy)phenyl]-2-methoxyiminoacetamide of log p=1.87.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[H-].[Na+].[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55]Br)=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.[Cl-].[Na+].O>[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55][CH:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5](=[O:28])[N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:16]2=[O:17])=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (520 mg, 1.079 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 50 mg, 1.27 mmol). The reaction was stirred at 0° C. for 45 minutes and 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (423 mg, 1.36 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 24 hours and was diluted with brine. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (1×), dried (MgSO4), filtered and concentrated in vacuo to provide 3-(6-{[isopropyl-(6-methoxy-pyridin-3-yl)-carbamoyl]-methyl}-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl)-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 8.05 (d, 1H), 6.80-7.75 (m, 15H), 4.75 (m) and 4.60 (t, total 3H), 3.85-4.20 (m, 6H), 1.65 (m, 9H), 0.98 (m, 6H); MS 713.6 (M+1), 711.5 (M−1).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=O)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[NH2:27][C:28]([NH2:30])=[S:29].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(#N)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[S:29][C:28]([NH2:30])=[N:27][C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(N)=S
Reactant: Cc1cccc(C(=O)Cc2ccnc(F)c2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Bromine (1.9 mL, 37 mmol) was added to a solution of 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (8.5 g, 37 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. Triethylamine (5.2 mL, 37 mmol) was added to a mixture of this residue and thiourea (3.0 g, 40 mmol) in acetonitrile (50 mL) and the mixture was stirred at 80° C. for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the reaction mixture and the precipitated solid was collected by filtration. After the resulting solid was washed with water, it was dried. The crude crystals were recrystallized from ethanol to obtain 3.7 g (yield 35%) of the title compound.
Reaction SMILES: C(Cl)Cl.C(N(CC)CC)C.[B]1OC(C)(C)C(C)(C)O1.I[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[O:27]1[C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][C:23]=2[O:29][CH2:28]1
Reactant: Ic1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)O[B]OC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To 28 mg PdCl2(dppf).CH2Cl2 in a reaction tube under nitrogen were added 4 ml dioxane, 0.43 ml (3 mmol) triethylamine, 0.23 ml (1.5 mmol) pinacolborane and 262 mg (1.06 mmol) 1-iodo-3,4-methylenedioxybenzene. The reaction solution was warmed to 80° C. with stirring in an oil bath for 22 h. An aliquot (0.3 ml) was removed from the reaction and extracted into ethyl acetate and washed several times with water and analysed by gc (fid detector, SGE HT5 capillary column). All the 1-iodo-3,4-methylenedioxybenzene had reacted to form the boronic acid ester together with some 1,3-benzodioxole. After addition of 8 ml methanol (which destroys the excess pinacolborane and thereby prevents the formation of symmetrical biaryl), 1.07 g Cs2CO3 and 261 mg (1.06 mmol) 4-iodobenzamide, the solution was warmed to 40° C. for 17 h. An aliquot (0.5 ml) was removed from the reaction solution and extracted into ethyl acetate and washed several times with water and analysed by gc (fid detector, SGE HT5 capillary column). The required biaryl (identified by gc/ms) gave rise to the strongest peak in the gc trace.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([O:11][C@H](C1C=CC=CC=1)C)=[O:10]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([OH:11])=[O:10]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N1CCCCC1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1F)N1CCCCC1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate (0.737 g, 2.16 mmol) and 20% Pd(OH)2/C (0.070 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 2 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This provided the title compound as a colorless solid (0.503 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H). LCMS: Anal. Calcd. for C13H16FNO2: 237; found: 238 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=O)C.[CH2:17]1[CH:19]([C:20]([NH2:22])=[NH:21])[CH2:18]1.Cl.CC(C)([O-])C.[K+]>CO>[CH:19]1([C:20]2[N:22]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:21]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)C1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Oc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution consisting of 3-(3,4-dichlorophenyl)-3-oxo-propionic acid ethyl ester (252 mg, 0.967 mmol) and MeOH were added cyclopropylcarbamidine hydrochloride (140 mg, 1.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol). The reaction mixture was stirred at rt overnight, then concentrated. Water and CH2Cl2 were added, and the mixture was adjusted to pH 7 with glacial acetic acid. The layers were separated, and the aqueous phase was extracted with EtOAc. The organics were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (133 mg, 49%).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH3:28])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH3:28]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16, Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes, to give the desired product (1.01 g, 60%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]([CH2:39][C:40]([OH:42])=[O:41])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>CC(=O)OCC>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]([CH2:39][C:40]([OH:42])=[O:41])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:11][CH2:10]1
Reactant: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(CC(=O)O)c2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(N)CC3)n(CC(=O)O)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a solution of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid (100 mg, 0.15 mmol) in EA (10 mL) was added a 5N HCl solution in EA (5 mL). The reaction mixture was stirred at RT for 2 h, and the solvent was concentrated in vacuo. The residue was purified by preparative HPLC to give 25 mg of the title product as HCl salt (32%). 1H NMR (400 MHz, CD3OD): δ 1.53-1.56 (m, 2H), 2.00-2.03 (m, 2H), 3.00-3.07 (m, 2H), 3.35-3.39 (m, 1H), 3.67 (s, 3H), 4.70 (s, 2H), 4.76-4.77 (m, 2H), 6.74 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.26 (d, J=10.0 Hz, 1H), 7.50 (dd, J=7.2, 8.0 Hz, 1H). [M+H] Calc'd for C25H24FN5O4, 478. Found, 478.