Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(trifluoromethyl)phenylboronic acid (1.63 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3) 4 (0.497 g, 0.430 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (0.22 g, 0.739 mmol, yield 9%) as a brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:27]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(C3CCN(CCCCn4nnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.9 g compound (I-156) with a yield of 60.1%. ESI-MS [M+H]+: m/z 385.3.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=O)[CH:13]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[N:1]1([CH2:6][C:8]2[CH:9]=[C:10]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]([CH2:14][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)N2CCCC2)c1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc2c(Nc3cc(CN4CCCC4)cc(CN4CCCC4)c3)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
To a suspension of N-{3,5-bis[(pyrrolidin-1-yl)carbonyl]phenyl}-7-chloroquinolin-4-amine (84 mg, 0.19 mmol) in 15 mL of anhydrous THF, was added portionwise LiAlH4 (71 mg, 10 eq). The reaction mixture was stirred at room temperature for 2 h and then 10 mL of ethyl acetate was added. The mixture was filtered through a celite pad. The filtrate was evaporated and the residue was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound (4 mg, 5%) as a yellow oil. m/z (ESI) 420.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].[H][H]>[Pt]=O.C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1)[CH3:2]
Reactant: CCOC(=O)CN(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CN(CCCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C

Procedure:
A solution of 2-7 (24.3 g, 65.1 mmol), platinum oxide (4 g) and ethanol (130 mL) was stirred under a balloon of hydrogen gas for 6 h. Following filtration and evaporation, the residue was chromatographed (silica gel, ethyl acetate) to give 2-8 as a yellow oil. TLC Rf =0.35 (silica, 70:25:5 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 7.05 (d, 1H, J=6 Hz), 6.37 (m, 1H), 4.74 (brs, 1H), 4.18 (q, 2H, J=7 Hz), 3.9 (2s, 2H), 3.32 (m, 4H), 2.63 (m, 2H), 2.51 (m, 2H), 2.72 (m, 4H), 1.43 (m, 9H), 1.26 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[C:7](N=[N+]=[N-])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O.O1CCOCC1>[C:7]([NH:1][CH2:2][CH2:3][OH:4])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a cooled, stirred solution of 2-aminoethanol (5.9 ml, 0.098 mol) and sodium hydroxide (3.6 g, 0.098 mol) in water-dioxane (1:1), was added drop-wise Boc-azide (10 ml, 0.081 mol). The reaction was stirred at room temperature overnight. The dioxane was then removed under vacuum, and the water layer extracted several times with ethyl acetate. The organic layer was dried over sodium sulphate and then, evaporated to dryness under vacuum to get the product (N-Boc)-2-aminoethanol (5.37 g, 41% yield), which was used in further steps without purification.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][NH:30][CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.Br[CH2:36][CH2:37][OH:38].C(N(CC)CC)C>CN(C)C=O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][N:30]([CH2:36][CH2:37][OH:38])[CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: OCCBr
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(CCO)C2)C3)c2ncnc(N)c12
Temperature: 85 °C
Yield: 48.7 %

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile (0.015 g, 0.034 mmol) (from Example 46, Step 15) and 2-bromoethanol (0.0097 mL, 0.14 mmol) were combined in N,N-dimethylformamide (1 mL) with triethylamine (0.019 mL, 0.14 mmol) at room temperature. The reaction was heated to 85° C. and after heating for 2 hrs the reaction was concentrated in vacuo and the residue was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the desired compound as a white amorphous solid (0.008 g, 50%). LCMS calculated for C23H28ClN8O2 (M+H)+: m/z=483.2; found: 483.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([C:46](=[O:48])[CH3:47])[CH2:41][CH2:42]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 44.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-piperazin-1-yl-ethanone hydrochloride (90 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-acetyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 17a (80 mg, yield 45%) as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:16]=2)[CH:10]=[CH:11][CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=2)=[O:32])=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(NC(=O)c2cccc(Oc3ccc(Cl)cc3[N+](=O)[O-])c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(O)c1)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To the product from Example 174a (1.5 g, 3.0 mmol) in THF (25 mL) was added tetrabutylammonium fluoride (0.94 g, 3.6 mmol). The reaction was stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.0 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1Cl
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1Cl
Yield: 30.4 %

Procedure:
Synthesized as described for 3 using 2-chloro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (5.0 g; 16.94 mmol), methyl 3-aminothiophene-2-carboxylate (2.93 g; 18.63 mmol), 4-dimethylaminopyridine (517.0 mg; 4.23 mmol) pyridine (38.0 mL; excess) and anhydrous dichloromethane (100 mL). The resulting crude white crystalline solid was washed with acetone to afford the title compound as a white solid (2.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH3:26]>>[O:34]=[C:28]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32]
Reactant: CCCNC(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-propyl-succinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-oxo-4-(propylamino)butanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=455; RT=1.18 min; UPLC Method I
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[CH:20][CH:21]=1)[C:18]#[N:19])#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(C#N)c(C#N)c1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncc(F)c3)no2)cc1C#N

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and product of Example 60A (76 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.71 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.19 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.37 (dd, J=8.2, 2.7 Hz, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]([C:22]([CH3:24])=[O:23])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])([O-:3])=[O:2].[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:29].N1CCCCC1>C(O)C>[NH2:29][C:28]1[O:23][C:22]([CH3:24])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])[CH:7]([C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCCCCCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)OC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.7 g (15 mmol) of decyl 2-(3-nitrobenzylidene)acetoacetate and 1.8 g (15 mmol) of ethyl cyanoacetate in 15 ml of ethanol was heated to boiling in the presence of 0.3 ml of piperidine, for 4 hours. The solvent was then removed by distillation and the oily residue was purified by column chromatography (SiO2, chloroform) and brought to crystalli ation, melting point: 100° C., yield: 3.3 g (45%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[OH:19][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCO)CC2)cc1
Yield: 69 %

Procedure:
A mixture containing 4-(4-methyl-benzyl)-piperidin-4-ol (5.1 g, 25 mmol), 2-bromoethanol (1.8 ml, 25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 2-butanone (120 ml) was refluxed for 22 hours. H2O (30 ml) was added and the aqueous phase was extracted with ethylacetate. Combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 9:1 +NH4OH (1%)) to provide 1-(2-hydroxy-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (4.3 g, 73%) as a yellow oil, MS: m/e=235.3 (M+).
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a water cooled (25° C.) solution of 10.0 g of (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 250 ml of dry methylene chloride is added in one portion 16.0 g of pyridinium chlorochromate, 36.0 g of dried, crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid. The resulting mixture is stirred at 25° C. for one hour. Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added, the suspension is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in diethyl ether and is passed through a short column of silica gel using diethyl ether as the eluant. The first two 500 ml fractions contain the desired aldehyde. The solvent is concentrated in vacuo to give 10.1 g of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:9])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 60 °C

Procedure:
(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine (468 mg, 1.41 mmol) and K2CO3 were dissolved in DMF (10 mL). Methyl bromoacetate (0.67 mL, 7.08 mmol) was added and the reaction was heated at 60° C. for 2 h. The mixture was cooled and diluted with EtOAc. The organics were washed with water (2×) and dried over MgSO4. The title compound was purified by preparative RPLC. 1H NMR (DMSO-d6) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.05 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.71 (s, 3H), 3.50 (s, 3H), 2.58 (s, 3H); LC-MS (ESI+; 338 ([M+H]+)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:35][CH2:36][N:37]([S:40]([CH3:43])(=[O:41])=[O:42])[CH2:38][CH2:39]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CS(=O)(=O)N1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-(methylsulfonyl)piperazine. MS (ESI): mass calcd. for C21H22FN5O4S2, 491.11; m/z found, 492.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.23 (s, 1H), 8.13 (d, J=7.0, 1H), 7.97 (m, 1H), 7.77-7.71 (m, 1H), 7.67-7.61 (m, 1H), 7.46 (d, J=6.4, 1H), 7.39-7.32 (m, 2H), 3.03-2.94 (m, 8H), 2.78 (s, 3H).
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Sodium iodide (3.9 g, 26 mmol) and hydriodic acid (10 mL, 47% aqueous solution) were added to the solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine (8.0 g, 26 mmol) and 4-aminobenzotrifluoride (5.06 g, 0.031 mol) in dioxane (100 mL) and the reaction solution was stirred at 100° C. overnight. Solid thus formed was filtered out, washed by ethyl acetate and diethyl ether and dried in vacuo. Product was obtained as white needle solid (8.2 g, 73%).
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Temperature: 50 °C

Procedure:
Sodium (1.11 g, 48.2 mmol) was dissolved in dry methanol (30 ml) and heated to 50° C. Dimethyl malonate (5.87 ml, 51.4 mmol) was added over 15 min. The mixture was heated to reflux and a suspension of 15-bromopentadecanoic acid (5 g, 15.6 mmol) in dry methanol (50 ml) was added over 45 min. The resulting mixture was refluxed for another 30 min. After cooling to RT, water was added and the mixture was concentrated. Water was added to the residue an made alkaline with 1 N NaOH and extracted with ether (1×50 ml). The aqueous layer was acidified with 1N HCl and extracted with ether (3×30 ml). The combined organic layers was dried (Na2SO4) and concentrated to give the title compound in 98% (5.7 g) yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18]>ClCCl>[CH3:15][NH:16][C:17]([NH:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[S:18]
Reactant: Cc1cccc(N2CCOCC2)c1N
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1c(C)cccc1N1CCOCC1

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) at room temperature for four days yielded N-methyl-N'-(6-methyl-2-morpholinophenyl)thiourea (m.p. 182°-183° C.).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>CC#N>[CH3:43][C:37]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([C:25]2[N:24]([CH3:32])[N:23]=[CH:22][C:21]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9]2[N:19]([CH:20]=[C:7]([C:5]4[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=[C:2]([CH3:1])[N:6]=4)[N:8]=2)[CH2:18][CH2:17][O:16]3)[CH2:27]1)([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCCC(c2c(-c3ccc4c(c3)OCCn3cc(-c5nc(C)nn5C(C)C)nc3-4)cnn2C)C1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (60 mg, 0.127 mmol), ethyl 2-bromo-2-methylpropanoate (247.65 mg, 1.27 mmol), Ag2O (294 mg, 1.27 mmol), H2O (0.1 ml) and CH3CN (1.5 ml) in a seal tube was heated at 60° C. for 8 h. The solid was filtered off and the filtrate was purified by Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford ethyl 2-methyl-2-[3-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)piperidin-1-yl]propanoate (35 mg, 47% yield). LCMS (ESI) m/z: 589.3 [M+H+]