Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:26]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:27]1
Reactant: OC1CCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@H]4CC[C@H](O)C4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and 1,3-cyclopentanediol (mixture of isomers, cis:trans=ca. 5:1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:20]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
3-Fluoro-4-hydroxyphenylacetic acid (170 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice-bath N-Hexylbenzylamine (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 mmol). The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (×2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 265 mg the desired product, yield 77%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([CH:10]=[O:11])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]2[CH:27]=[C:26]([CH:28]=[O:29])[C:25]([O:30]C)=[CH:24][C:23]=2[CH3:32])[CH:15]=[CH:14][CH:13]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:32][C:23]1[CH:24]=[C:25]([OH:30])[C:26]([CH:28]=[O:29])=[CH:27][C:22]=1[C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[C:3]2[CH:4]=[C:5]([CH:10]=[O:11])[C:6]([OH:8])=[CH:7][C:2]=2[CH3:1])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(C)c(-c2cccc3cccc(-c4cc(C=O)c(OC)cc4C)c23)cc1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(C=O)cc1-c1cccc2cccc(-c3cc(C=O)c(O)cc3C)c12
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 1,8-bis(2′-methyl-4′-methoxy-5′-formylphenyl)naphthalene, 8, (0.78 g, 1.9 mmol) in 35 mL of anhydrous CH2Cl2 at 0° C., BBr3 (11.8 mL, 11.8 mmol) was added dropwise and the mixture was stirred for six hours. The reaction was carefully quenched with isopropyl alcohol followed by addition of water, and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 20:1) afforded 0.58 g of 5 (1.5 mmol, 77%) as a white solid. The anti/syn-ratio was determined as 20:1 by 1H-NMR spectroscopy. Enantiopure anti-5 was obtained via formation of 9 or 10 as described below and hydrolysis or by asymmetric transformation of the first kind and subsequent hydrolysis (see SI).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([CH3:28])=[CH:21][N:20]=1>O1CCCC1>[CH3:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Yield: 37.4 %

Procedure:
2-(2-Cyanoethyl)malonic acid diethylester (40 g) was reacted with sodium hydride (4.4 gm) in tetrahydrofuran at 20° C. 2-Chloro-5-methyl-3-nitro-pyridine (35 g) was added and the internal temperature was raised to 100° C. (some tetrahydrofuran distilled off) over 4.25 hrs. The reaction mixture was partitioned between chloroform and water and treated with charcoal. Vacuum distillation of the chloroform extract and then chromatography (CHCl3, silica column) of the distillation residues gave 4-(5-methyl-3-nitropyrid-2-yl)-4,4-bis (carbethoxy)-butyronitrile (24.5 g) as a yellow solid m.p. 48°-49° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1C(F)(F)F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example A7, 14.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 1.6 l of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:36]([CH3:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[CH3:38])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:38])=[CH:31][C:32]([C:33]#[N:34])=[CH:35][C:36]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2c1ccn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 4-aminobenzonitrile (54 mg, 0.46 mmol) in 1-methyl-2-pyrridone (1 mL) was added NaH (18 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (34 mg, 0.091 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 28 mg (65%) of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:13]([C:3]3[CH:4]=[N:5][N:6]([C:7]4[N:8]=[CH:9][CH:10]=[CH:11][N:12]=4)[C:2]=3[Cl:1])=[O:15])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cnn(-c2ncccn2)c1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cnn(-c2ncccn2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-adamantan-1-ylmethan-amine (36 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 18 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo to give a reddish/brown oil. Purification by silica gel column chromatography (gradient from 90% EtOAc/hexane to EtOAc) affords the title compound as a light reddish/brown solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (2H, d, J 4.8), 8.28 (1H, s), 7.41 (1H, t, J 4.8), 6.47 (1H, bs), 3.18 (2H, d, J 6), 2.01 (3H, s), 1.69 (6H, m), 1.58 (6H, s). MS (M+1)=372.19; RT=1.31 min. *IC50.
Reaction SMILES: C([Si](C)(C)OC(CC1C=CC=CC=1)CCC1NC(=O)CC1)(C)(C)C.C([Si](C)(C)[O:30][CH:31]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][C:36](=[O:39])[N:35]1[CH2:40][CH2:41][CH2:42][C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:30][CH:31]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][C:36](=[O:39])[N:35]1[CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:47]#[N:48])=[CH:49][CH:50]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 79.8 %

Procedure:
Analogous to the procedure described for Compound 1A, Step E, 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg, 0.525 mmol) was deprotected with TBAF (1M in THF, 0.79 mL, 0.79 mmol) over 24 h. Purification by medium pressure chromatography (1:1 EtOAc: hexanes to EtOAc to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2) provided 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzonitrile (157.8 mg). 1H NMR (CDCl3) δ 7.56 (m, 2H), 7.26 (m, 7H), 3.80 (m, 1H), 3.67-3.55 (m, 2H), 2.98 (m, 1H), 2.80 (m, 1H), 2.65 (t, 2H), 2.43-2.24 (m, 2H), 2.08 (m, 1H), 1.89-1.33 (m, 9H); MS 375.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:33][CH:34]=3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: N[C@@H]1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (3R)-1-[bis-(4-chlorophenyl)methyl]-3-aminopyrrolidine (2.05 g, compound obtained in Reference Example 11) and triethylamine (1.35 mL) in methylene chloride (30 mL) was added dropwise 4-(trifluoromethoxy)benzoyl chloride (1.21 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and the mixture is extracted with chloroform (×2). The organic layer was filtered through a NH-silica gel (10 g of Chromatorex NH-silica gel; Fuji Silicia Chem.) and the filtrate was evaporated in vacuo. The crude product was triturated in ethyl acetate/hexane to obtain (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (2.70 g; yield: 83%) as crystals.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[C:26]([Cl:32])[C:25]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1.C(O)(=O)C.C([BH3-])#N>ClCCCl.CO>[Cl:23][C:24]1[C:25]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[C:26]([Cl:32])[CH:27]=[C:28]([CH2:30][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)[CH:29]=1
Reactant: O=Cc1cc(Cl)c(-c2ccc(F)cc2)c(Cl)c1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(-c5ccc(F)cc5)c(Cl)c4)CC3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate (27 mg, 0.084 mmol) (from Example 1-1, Step 2) and 2,6-dichloro-4′-fluorobiphenyl-4-carboxaldehyde (15 mg, 0.056 mmol) (from Step 3) in DCE (2 mL) and methanol (2 mL) in a 20 mL scintillation vial was added acetic acid (10 uL, 0.168 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 18 hours and was then filtered to remove the resin. The volatiles were removed in vacuo and the residue was used directly in Step 5
Reaction SMILES: NC[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].ClC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[N+:12]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:3]=1)[C:7]([OH:9])=[O:8])([O-:14])=[O:13]
Reactant: NCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 92 %

Procedure:
4-(Aminomethyl)-3-nitrobenzoic acid G (0.8 g; 4 mmol) was dissolved in 10% aq. Na2CO3 (25 mL) and 1,4-dioxane (10 mL) and the solution was cooled to 0° C. A solution of 9-fluorenylmethyl chloroformate (Fmoc-Cl) (1.06 g; 4 mmol) in 1,4-dioxane (10 mL) was added dropwise for 20 min. After 2 h at 0-5° C. and 1 h at 10° C. the reaction mixture was filtered and the solution was acidified to pH 5 by addition of 1 N HCl. The precipitate was filtered, washed with H2O (2×2 mL) dried under vacuum (1.3 kPa; P2O5) to give 4-[[[9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl]-3-nitrobenzoic acid as a white solid (1.6 g; 3.7 mmol). Yield 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[N:22][C:23]([CH3:27])=[N:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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].C(Cl)Cl>[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=3[O:2][CH3:1])=[N:22][C:23]([CH3:27])=[N:24]2)=[CH:19][CH:18]=1
Reactant: Cc1nc(Cl)c2ccc(Br)cc2n1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.159 g, 0.194 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.940 g, 4.27 mmol), 7-bromo-4-chloro-2-methylquinazoline (ACES Pharma, 1.000 g, 3.88 mmol), and potassium carbonate (2.147 g, 15.53 mmol) in 12 mL dioxane was treated with 4 mL water and was allowed to stir overnight at room temperature. LC/MS showed mostly product, so the aqueous layer was removed, and the reaction mixture was concentrated. Purification of the crude residue by silica gel column chromatography (0-50% EtOAc/heptane) gave 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylquinazoline (0.797 g, 2.007 mmol, 51.7% yield). (M+H)+=396.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[C:22](I)=[CH:21][C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:19][N:8]2[C:9](=[O:18])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH2:31].N#N.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[C:22]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH2:31])=[CH:21][C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:19][N:8]2[C:9](=[O:18])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)c1nc2c(I)cc(N3CCOCC3)cn2c(=O)c1Cc1ccccc1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: C=C(OCCCC)c1cc(N2CCOCC2)cn2c(=O)c(Cc3ccccc3)c(C(=O)OC)nc12
Yield: 58.9 %

Procedure:
3-Benzyl-9-iodo-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (1 g, 1.92 mmol), n-Butyl vinyl ether (961 mg, 9.59 mmol), 1,3-Bis(diphenylphosphino)propane (DPPP) (24 mg, 0.058 mmol), Pd(OAc)2 (11 mg, 0.048 mmol) were mixed in DMF (15 ml). The mixture was heated at 80° C. under the atmosphere of N2 overnight, after which water was added and then extracted with dichloromethane. The extracts were combined, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography to give the desired product (540 mg, yield 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[F:40])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1COCC1>[Si:12]([O:19][CH2:20][CH2:21][N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[F:40])[C:8]([C:7]1[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1])=[O:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COC(=O)CC1CCC(c2ccc(NCCO[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Solvent: C1CCOC1
Product: COC(=O)CC1CCC(c2ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4,6-dichloropyrimidine-5-carbonyl chloride (82.5 mg, 0.390), methyl 2-(4-(4-(2-(tert-butyldimethylsilyloxy)ethylamino)-3-fluorophenyl)cyclohexyl)acetate (110 mg, 0.26 mmol) and TEA (0.054 mL, 0.39 mmol) in THF (2 mL) was stirred at room temperature under nitrogen for 14 hours. The reaction mixture was concentrated to remove THF. The residue was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated. The crude material was purified by a 12 g silica gel column eluted with 3-15% EtOAc in heptane to give methyl 2-(4-(4-(N-(2-(tert-butyldimethylsilyloxy) ethyl)-4,6-dichloropyrimidine-5-carboxamido)-3-fluorophenyl)cyclohexyl)acetate a colorless oil (60 mg). m/z=598.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:22]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][C:21]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)=[O:22])([O:29][CH3:30])=[O:28]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Reactant: COC(=O)CCCCC(=O)Cl
Product: COC(=O)CCCCC(=O)n1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(5-Carbomethoxypentanoyl)-3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl 5-(chloroformyl)pentanoate.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6]C(N)=N.N([O-])=O.[Na+].[NH:14]1[C:21](=[O:22])[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16].Cl.N(C(N)=[NH2+])=[N+]=[N-]>O.Cl>[N+:5](=[C:20]1[C:18](=[O:19])[NH:17][C:15](=[O:16])[NH:14][C:21]1=[O:22])=[N-:6]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=C1C(=O)NC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
29.9 g (0.22 mol) of aminoguanidine bicarbonate are dissolved in a mixture of 150 ml of water and 54 ml of 10N hydrochloric acid, and the solution is cooled to 0° C. by adding ice. 50 ml of an aqueous solution of sodium nitrite containing 30 g of dissolved sodium nitrite per 100 ml are added dropwise to this mixture in the course of about 15 minutes. After 5 minutes, a nitrite excess which may be present is removed using amidosulphonic acid. 25.6 g (0.2 mol) of barbituric acid are thrown into the solution of azidoformamidinium hydrochloride thus obtained, and the mixture is heated at 70° C. for 4 hours and at 95° for 1 hour. The solution is then cooled down to 0°-5°, the precipitate is filtered off with suction and washed with ice-cold water. Drying at 70° in a through-circulation cabinet gives 27.8 g (90.2%) of diazobarbituric acid of the formula ##STR8##
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]=[C:14]([N:27]1[CH2:31][C:30]2=[CH:32][S:33][CH:34]=[C:29]2[CH2:28]1)[CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCCC1>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:17](=[O:19])[CH:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][C:14]([N:27]2[CH2:31][C:30]3=[CH:32][S:33][CH:34]=[C:29]3[CH2:28]2)=[O:13])[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(CC(=O)N2Cc3cscc3C2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
0.55 g (3.39 mmol) of carbonyldiimidazole is added to a solution of 1 g (3.17 mmol) of γ-oxo-α-(phenylmethyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-butanoic acid in 15 ml of dry tetrahydrofuran. The solution is stirred at room temperature for 1 h and then 0.42 ml (3.8 mmol) of 4-methylpiperazine is added and the solution is stirred at room temperature for 20 h. The mixture is then evaporated to dryness, the residue is dissolved in 50 ml of dichloromethane, and then the solution obtained is washed successively with twice 50 ml of a saturated sodium hydrogen carbonate solution and 20 ml of a saturated sodium chloride solution, dried over sodium sulphate and then evaporated to dryness. After recrystallization from ethanol, 1 g of a white solid is obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(F)(F)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.