Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.C(N(CC)CC)C.C1[O:45][CH:44]1CO.[CH3:48][CH2:49][OH:50]>CCOC(C)=O>[OH:50][CH:49]([CH2:44][OH:45])[CH2:48][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[CH3:27])=[CH:30][CH:31]=1
Reactant: CCO
Reactant: OCC1CO1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCC(O)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Yield: 27 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (37, 50 mg, 0.10 mmol) in EtOH (1 mL) under nitrogen was added triethylamine (1.4 μL, 0.010 mmol) and glycidol (10 μL, 0.15 mmol). The reaction was heated at 80° C. overnight, then recharged with triethylamine and glycidol and heated at 90° C. for 5 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The material was purified twice by prep HPLC (C18 30×100 mm column, 20-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to provide diol 53 as a white solid (12 mg, 27% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10-7.19 (m, 3 H), 7.05 (d, J=8.8 Hz, 2 H), 6.81-6.88 (m, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 3.89-4.05 (m, 5 H), 3.59-3.71 (m, 2 H), 3.35-3.49 (m, 3 H), 2.20 (s, 3H), 2.14 (s, 3 H); MS (ES+) [M+NH4]+=468.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C-:10]#[N:11].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10]([CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])#[N:11]
Reactant: N#Cc1ccsc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1sccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
2-Bromomethyl-3-cyanothiophene (2.746 g) was dissolved in toluene (40 ml), followed by the addition of a solution of sodium cyanide (2.002 g)/water (15 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow solid (823 mg, yield; 43%).
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38](=O)[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2/[C:38](=[CH:7]/[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccc(Br)cc2COc2ccccc21
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC/C=C1/c2ccc(Br)cc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane, and 8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an E/Z (1:3.5) isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z-isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 7.38-7.44 (m, 2H, H7 and H9); 7.13-7.18 (m, 3H, aromatic H); 6.84-6.93 (m, 2H, H2 and H4); 5.70 (t, 1H, CH=); 5.15 (br s, 2H, ArCH2O); 2.55 (q, 2H, CH2); 2.43 (t, 2H, NCH2 ); 2.22 (s, 6H, NMe2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][N:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[N:20][C:19]=12.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:29][N:27]1[CH:28]=[C:24]([C:22]2[CH:21]=[N:20][C:19]3[N:18]([N:17]=[CH:16][C:15]=3[C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:23]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3c(Br)cnn3c2)cn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cnn3cc(-c4cnn(C)c4)cnc23)cc1
Temperature: 85 °C

Procedure:
[4-(Methoxycarbonyl)phenyl]boronic acid (0.5 g, 2.77 mmol) was added to 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (0.7 g, 2.52 mmol). DMF (12.5 mL) and 1M Na2CO3 (3.8 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.15 g, 0.13 mmol) was added in a counter flow of nitrogen. The reaction mixture was heated to 85° C. for 16 h, cooled, and poured into a 5-fold excess of water. The solids were filtered and dried to give crude methyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoate: LC/MS [M+H]=334.0.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]2[C:19]([O:20][C:21]3[CH:28]=[C:27]([CH3:29])[C:24]([C:25]#[N:26])=[C:23]([CH3:30])[CH:22]=3)=[CH:18][NH:17][N:16]=2)[CH2:14][CH2:13]1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH:12]1([C:15]2[C:19]([O:20][C:21]3[CH:28]=[C:27]([CH3:29])[C:24]([C:25]#[N:26])=[C:23]([CH3:30])[CH:22]=3)=[CH:18][N:17]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[N:16]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(Oc2c[nH]nc2C2CC2)cc(C)c1C#N
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc(Oc2cn(C3CCCCO3)nc2C2CC2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.1 %

Procedure:
p-Toluenesulphonic acid (20 mg, 0.12 mmol) was added to a solution of the benzonitrile of Example 16 (1 g, 3.94 mmol) in tetrahydrofuran (30 ml). 3,4-Dihydro-2H-pyran (664 mg, 7.9 mmol) was then added dropwise at room temperature. The reaction mixture was stirred at room temperature, under nitrogen, for 15 hours. It was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate (50 ml). The organic layers were washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure to provide the title compound (1.93 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([OH:13])[CH2:8][CH2:7][CH2:6]2>C(Cl)Cl.CC#N.O=[Mn]=O>[OH:13][C@H:9]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:2]=[O:1])[CH:12]=[CH:11][C:10]1=2
Reactant: OCc1ccc2c(c1)CCC[C@@H]2O
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2.5 g, 14 mmol) in CH2Cl2/MeCN (1:1, 80 mL) was added MnO2 (6.1 g, 70. mmol). The reaction mixture was stirred for 16 h at RT. The solid was filtered off, and the filtrate was concentrated to afford the title compound. MS (m/z): 277.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([SH:11])=[N:8][C:7]=2[CH:12]=1.[CH2:13](N(CC)CC)C.IC>C(O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:13])=[N:8][C:7]=2[CH:12]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2sc(S)nc2c1
Solvent: CI
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccc2sc(SC)nc2c1
Yield: 103.4 %

Procedure:
5-Methoxy-2-mercaptobenzothiazole (18.3 g, 0.1 mol) was dispersed in 125 ml 95% ethanol. Addition of 10.1 g (0.1 mol) triethylamine gave a brown solution. Addition of iodomethane (14.2 g, 0.1 mol) was slightly exothermic. Additional heating brought the mixture to reflux for 2 hours. After cooling, the residue was dispersed in isopropanol and filtered to remove triethylammonium iodide. The filtrate was mixed with water and the layers separated. The aqueous phase was extracted 3×50 ml methylene chloride. The organic portions were combined, washed and brine, and dried with Na2SO4. Filtration and rotary evaporation yielded 21.85 g brown liquid which was distilled at 158°-162° C. (0.125 mm) to give 16.73 g (85%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:14])[CH2:9]1.[NH:35]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:3][C:2]1[N:35]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)[C@H]3CCNC3)cc2)CC1
Product: Cc1ccc(N2CC[C@H](C(=O)Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-bromo-6-methylpyridazine for 3-bromopyridine and (S)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][CH:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=413.5 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:23]#[C:24]Br>>[F:22][C:18]1[CH:17]=[C:16]([N:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: N#CBr
Reactant: COc1ccc(CN(C[C@H](N)CO)c2cccc(F)c2)cc1
Product: COc1ccc(CN(C[C@H]2COC(N)=N2)c2cccc(F)c2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(3-fluoro-phenyl)-(4-methoxy-benzyl)-amino]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-{[(3-fluoro-phenyl)-(4-methoxy-benzyl)-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Light yellow gum. MS (ISP): 330.3 ([M+H]+)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[C:32]([C:34]1[C:35]([CH3:51])=[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][NH2+:48][CH2:49][CH2:50][N:43]3[CH2:42]2)[CH:37]=[CH:38][C:39]=1[F:40])#[N:33].[N:52]1([C:57]2[N:62]=[CH:61][C:60]([CH2:63][C:64](O)=[O:65])=[CH:59][N:58]=2)[CH:56]=[N:55][N:54]=[N:53]1.C(N(CC)CC)C>CN(C=O)C>[F:40][C:39]1[C:34]([C:32]#[N:33])=[C:35]([CH3:51])[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][N:48]([C:64](=[O:65])[CH2:63][C:60]4[CH:59]=[N:58][C:57]([N:52]5[CH:56]=[N:55][N:54]=[N:53]5)=[N:62][CH:61]=4)[CH2:49][CH2:50][N:43]3[CH2:42]2)=[CH:37][CH:38]=1
Reactant: Cc1c([C@H]2CN3CC[NH2+]C[C@H]3CO2)ccc(F)c1C#N
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HATU (192 mg, 0.504 mmol) was added to a solution of (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (104 mg, 0.504 mmol) in DMF (1.5 mL). The reaction mixture was stirred at RT for 15 minutes and a solution of [2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetic acid (284 mg, 0.564 mmol) and triethylamine (0.37 ml, 2.65 mmol) in DMF (1 mL) was added. The flask was rinsed with DMF (0.5 mL). The solution was stirred at RT overnight then diluted with EtOAc and washed with dilute NaHCO3 solution, water (3×) and brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by silica gel chromatography (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 column volumes and holding at 60% A for 2 column volumes to afford the title compound: LC/MS: 505 (M+CH3CN+Na), 464 (M+H). The title compound was converted to its hydrochloride salt by dissolving in methylene chloride and adding 1 equivalent 1M HCl in ether. The suspension was stirred at RT for 30 minutes and the solvent evaporated: NMR 500 MHz (CD3OD(mixture amide rotamers) 10.03 (s, 1H); 8.87 (s, 1H); 8.86 (s, 1H); 7.94 (q, 1H); 7.31 (d t, 1H); 5.08-5.15 (m, 1H); 54.68 (d, 0.5H); 4.60 (d, 0.5H); 4.01-4.38 (m, 5.5H); 3.82 (t, 2H); 3.58-3.71 (m, 1.5H); 3.40-3.53 (m, 2.5H); 3-31-3.37 (m, 1.5H); 2.61 (br s, 3H); LC/MS 527 (M+Na+CH3CN), 505 (M+H+CH3CN), 486 (M+Na), 464 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0471 g, 0.261 mmol) synthesized in Example B9, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-chloro-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:6]=[C:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=4)=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)cc(C)n1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)cc(C)n1

Procedure:
To a solution of intermediate 20 (1.066 mmol) in 1,4-dioxane (4.5 ml) and a saturated solution of NaHCO3 (4.5 ml) was added intermediate 5 (0.23 g, 0.906 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.12 mg, 0.106 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 50% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 9 that was precipitated from diethylether (0.144 g, 42%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:29])[CH2:25][C:26](O)=[O:27])[CH2:20][CH2:19]1.CC(C)N=C=NC(C)C>C1COCC1>[Cl:14][C:15]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:29])[CH2:25][C:26]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)=[O:27])[CH2:20][CH2:19]1
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cn1
Yield: 18.7 %

Procedure:
To a stirred solution of 5-phenyl-pyridin-2-ylamine (0.041 g, 0.00024 mole) in THF (3 mL) was added 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid (0.08 g, 0.00025 mole) followed by DIC (0.036 g, 0.00028 mole). The mixture was heated to reflux for 3 hours, and then concentrated under educed pressure. The resulting residue was stirred with cold ether. The organic layers were removed by filtration and concentrated under reduced pressure to afford 0.021 g (18%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-N-(5-phenyl-pyridin-2-yl)-propionamide. LC-MS purity: 468.14 (M+1)+, 98%, 1H NMR (DMSO-d6) δ 11.2 (bs, 1H), 8.2 (t, 2H), 8.0 (d, 1H), 7.4 (m, 4H), 7.1 (t, 1H), 6.6 (d, 2H), 4.6 (s, 1H), 4.0 (d, 1H), 3.7 (m, 1H), 3.6 (m, 3H), 2.1 (bs, 9H), 1.8 (t, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Br[C:25]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:25]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc(C=O)c(Br)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-4-methylbenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(C(C)=O)C(C)C>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
Into a reaction vessel were charged 83.1 parts of 2-methyl-2-adamantanol and 101 parts of triethylamine, and 200 parts of methyl isobutyl ketone was added thereto to form a solution. To this solution was added dropwise 78.4 parts of methacryloyl chloride (1.5 male based on 2-methyl-2-adamantanol). The solution was stirred at room temperature for about 10 hours. After filtration, the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and then washed twice with water. The organic layer was concentrated and distilled under reduced pressure to give 2-methyl-2-adamantyl methacrylate represented by the following formula in 75% yield:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH:43]1([NH2:46])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:46][CH:43]1[CH2:45][CH2:44]1)=[O:24]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[O:13][C:12]=2[C:24]=1[CH2:25][OH:26].[Cl-].[NH4+].[CH2:29]([O:31][CH2:32][CH3:33])C.[O:34]1CCC[CH2:35]1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[O:13][C:12]=2[C:24]=1[CH2:25][O:26][CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:29]
Reactant: COc1ccc2c(c1)Oc1c(ccc(OC)c1CO)N2C
Reactant: C1CCOC1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: COCCOCOCc1c(OC)ccc2c1Oc1cc(OC)ccc1N2C
Reaction time: 0.5 h
Yield: 95.75 %

Procedure:
8.6 ml of n-butyllithium solution (1.6M in hexane) were added dropwise at -78° to a solution of 3.3 g (11.49 mmol) of 3,7-dimethoxy-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-methanol in 33 ml of absolute tetrahydrofuran, whereby a white precipitate formed. The reaction mixture was brought to 0°, stirred for 30 minutes, treated at 0° with 1.96 ml (1.5 eq.) of 2-(methoxyethoxy)methyl chloride, stirred at room temperature for 1 hour and then poured into ice, saturated ammonium chloride solution and diethyl ether. The organic phase was dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel with a mixture of ethyl acetate/hexane (1:2), whereupon, after drying in a high vacuum, 4.13 g (95.75%) of 3,7-dimethoxy-4-[[(2-methoxyethoxy)methoxy]methyl]-10-methyl-10H-dibenzo[b,e][1,4]oxazine were obtained as a colourless oil. MS: 375 (M+, 100), 360(11), 270(14), 256(21), 226(14).