Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH2:12]3)[CH:3]=1
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Oc2ccc3c(c2)CCN3)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 246 mg (1.0 mMol) of 5-(6-chloro-pyrimidin-4-yloxy)-1H-indole (WO 03/099771; Stage 163.1) in 5.5 ml acetic acid is cooled to 10-15° C. Then 314 mg (5 mMol) NaBH3CN are added portionwise. After 1 h stirring, 9 g of ice are added and the mixture is concentrated partially in vacuo. The residue is dissolved in 25 ml 1 N NaOH and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated at rt in vacuo: MS: [M+1]+=248; TLC(EtOAc/hexane 1:1): Rf=0.31.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:34]=[N:35][NH:36][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C)cn1)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 0.93 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 110) (57 mg, 0.178 mmol) and copper(I) iodide (3.40 mg, 0.018 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.2 mL) and the resulting mixture was treated with trimethylsilyl azide (0.095 mL, 0.714 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 2 h under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the residue partitioned between AcOEt and water. The layers were separated and the aqueous layer was extracted with AcOEt. The combined organic phases were washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP (modifier: ammonium bicarbonate) gave (2S,4R)-1-acetyl-2-methyl-N-(5-methyl-2-pyridinyl)-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (0.6 mg, 1.655 μmol, 0.928% yield) as a colourless solid.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:20]2[CH2:25][CH2:24][N:23]([C@H:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30]([C:32]3[C:33]([CH3:39])=[N:34][CH:35]=[N:36][C:37]=3[CH3:38])=[O:31])[CH2:22][CH2:21]2)[CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:9][CH:8]=1>CO>[C:4]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:20]2[CH2:21][CH2:22][N:23]([C@H:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30]([C:32]3[C:37]([CH3:38])=[N:36][CH:35]=[N:34][C:33]=3[CH3:39])=[O:31])[CH2:24][CH2:25]2)=[CH:11][CH:12]=1)(=[O:3])[NH2:1]
Reactant: COC(=O)COc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: N
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(OCC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
NH3 (g) was bubbled through a solution of {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester (see EXAMPLE 297) (54 mg, 0.095 mmol) in MeOH (10 mL) for 10 minutes. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give COMPOUND 298 as a pale brown solid (52 mg, 100%). 1H NMR (CDCl3) δ 0.89-1.12 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.52-1.63 (m, 1H), 1.74-1.78 (m, 3H), 2.13 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.72-2.84 (m, 3H), 3.27-3.40 (m, 2H), 3.79 (s, 2H), 3.85-3.89 (m, 1H), 4.40 (s, 2H), 5.59 (br s, 1H), 6.59-6.76 (m, 5H), 6.99 (s, 2H), 8.78 (br s, 1H), 8.86 (s, 1H). ES-MS m/z 551 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][C:43]([CH3:45])=[O:44].CO>C1COCC1>[CH3:42][C:43]([OH:44])([CH3:45])[CH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:3])=[O:4]
Reactant: CC(C)=O
Reactant: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 5-(2-methanesulfonyl-phenyl)-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0671 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide (0.20 mL, 0.201 mmol, 1.0 M solution in THF) at −78° C. After stirring for 30 min, acetone (0.2 mL) was added. The mixture was further stirred another 30 min. followed by an addition of MeOH to quench the reaction. Solvent evaporation provided a residue, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a white solid (0.030 g, 88%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.19 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.75-7.70 (m, 2H), 7.66-7.62 (m, 4H), 7.46 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.25 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.92 (s, 2H), 1.08 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H24F3N2O4S: 505.5 (M+H), Found 505.3.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:7]/[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(C)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: Cc1ccc(/C=C/c2ccc(C)cc2)cc1
Yield: 76 %

Procedure:
Reaction of 4-methylstyrene with Grubbs' second generation catalyst for 8.5 hours gave the title compound in 76% yield. The 1H and 13C NMR spectra agreed with those reported in the literature. 1H NMR (CDCl3): 2.34 (s, 6H), 7.03 (s, 2H), 7.14 (d, 4H, J=7.8 Hz), 7.39 (d, 4H, J=7.8 H13C NMR (CDCl3): 21.22, 126.29, 127.62, 129.34, 134.72, 137.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.CN(CCN(C)C)C.C([Li])CCC.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=[O:31].Cl>COC(C)(C)C.C(OCC)(=O)C.O>[NH2:8][C:5]1[C:4]([C:30](=[O:31])[C:29]([F:36])([F:35])[F:28])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: Nc1ncc(Cl)cc1C(=O)C(F)(F)F
Temperature: -20 °C

Procedure:
N-(5-chloro-2-pyridinyl)-2,2-dimethylpropanamide (20.0 g, 94.0 mmol) and TMEDA (12.0 g, 103 mmol) were dissolved in t-butyl methyl ether (150 mL), and while stirring the reaction solution at −20° C., n-butyl lithium (2.66 M hexane solution, 88.3 mL) was added dropwise thereto. After stirring the reaction solution at 0° C. for 2 hours, the solution was cooled to −78° C. and ethyl trifluoroacetate (16.8 mL, 140 mmol) was added thereto. The temperature of the reaction solution was raised to 0° C. and the solution was stirred for 3 hours. Then, water and 2 N hydrochloric acid were sequentially added, and the pH of the reaction solution was adjusted to about 9. After the solution was diluted with ethyl acetate, the organic layer was separated and the solvent was evaporated under reduced pressure. To the residue, acetic acid (60 mL), concentrated hydrochloric acid (20 mL) and water (40 mL) were added, and the solution was stirred for 10 hours under heating at 100° C. After the solution was cooled to room temperature, the resulting solid was collected by filtration and washed with ethyl acetate. The obtained solid and sodium acetate (7.64 g) were mixed in water (15 mL) and t-butyl methyl ether (70 mL), and the solution was stirred at room temperature for 30 minutes. The solution was diluted with ethyl acetate, which was then washed with water and saturated brine, and dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (10.1 g, 47.8%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1

Procedure:
To a solution of (R)-1-(6-amino-5-nitropyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.65 mmol) in ethanol (10 mL) was added palladium-on-carbon (0.2 g) in ethanol (10 mL) at room temperature. The mixture was subjected to a hydrogen atmosphere using a balloon filled with hydrogen gas. The mixture was filtered through Celite to afford the title compound. The filtrate was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[CH:11][C:12]([CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[CH:23]1([C:12]2[CH:11]=[C:10]([C:26]([O:28][CH3:29])=[O:27])[C:9]([OH:8])=[CH:14][C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:25][CH2:24]1
Reactant: [H][H]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1O
Yield: 95.8 %

Procedure:
A mixture of methyl 5-(benzyloxy)-2-cyclopropyl-2′,4′-difluorobiphenyl-4-carboxylate (20.3 g), 10% palladium carbon (containing 55% water, 10.0 g), and THF (100 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere of balloon pressure. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (15.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCCNc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
A mixture of 99.8 g (0.670 mol) 2,4-dichloropyrimidine, 52.8 g (0.703 mol) 3-amino-propan-1-ol and 135.6 g (1.34 mol) triethylamine was stirred at room temperature for 12 h. The residue was treated with a mixture of 500 ml saturated sodium carbonate solution and 1000 ml ethyl acetate. The organic phase dried (sodium sulphate) and evaporated to give an oil that solidified in the refrigerator overnight. The material was extracted with 200 ml ethyl acetate and the soluble fraction containing the 2-isomer evaporated (the 4-isomer remains insoluble in ethyl acetate). Chromatography on silica (ethyl acetate) gave 28.9 g (23%) of 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][C:20]=3[S:21][C:22]=2N(C)C)=[O:17])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH2:38]([O:45][CH2:46][C:47]1[CH:60]=[C:59](Br)[CH:58]=[CH:57][C:48]=1[O:49][CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:26][C:20]=3[S:21][C:22]=2[C:59]2[CH:58]=[CH:57][C:48]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56]3)=[C:47]([CH2:46][O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:60]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: Brc1ccc(OCCN2CCCC2)c(COCc2ccccc2)c1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(COCc4ccccc4)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield by essentially following the procedures outlined in Example 81, Part E, from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(4-morpholinyl)methyl]phenyl ketone (Example 49, Part C) and 1-[2-(2-benzyloxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][C:8]=1[F:22].[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[C:8]([F:22])[CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
Add butyllithium (7.3 mL, 11.7 mmol) to a solution of 4-bromo-N-(tert-butoxycarbonyl)-3-fluoro-benzylamine (1.55 g, 5.1 mmol) in diethyl ether (54 mL) at −78° C. under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (562 mg, 0.7 mL, 5.6 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (394 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH:23][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL) was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reaction mixture was stirred under nitrogen for 0.5 hour, then a solution of N,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL) was added dropwise over a period of 0.5 hour. The mixture was stirred at room temperature under nitrogen overnight. The reaction was diluted in volume to 350 ml and was then washed with 2N HCl (2×100 mL), saturated sodium bicarbonate (150 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to an oil. The crude oil was column chromatographed on silica gel with 10% ethyl acetate/hexane to remove impurities and the product eluted with 60% ethyl acetate/hexane to give the (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%). 1H (CDCl3) doublet 7.8 δ (2 ); multiplet 7.4 δ (7H); doublet 6.7 δ (2H); multiplet 6.0-6.2 δ (2H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 δ (3H); doublet 1.9 δ (3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])[C:15]#[N:16])=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC.O1CCCC1>[NH2:16][CH2:15][CH:14]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])[C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1
Reactant: N#CC(NCCCO)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC(NCCCO)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Prepare a suspension of lithium aluminum hydride in 1.0 liter of cold (-10° C.) ethyl ether with stirring. Add to the suspension a solution of 50 g of 4-fluoro-α-[(3-hydroxypropyl)amino]benzeneacetonitrile in 500 ml of ether and 100 ml of tetrahydrofuran under nitrogen. Stir the reaction mixture for five (5) hours at 0° C. then overnight at room temperature. Cool the reaction mixture to 0° C. and treat dropwise with 38 ml of water followed by 38 ml of 15% sodium hydroxide solution and 70 ml of water. Stir the reaction mixture for one-half hour, filter and concentrate to a solid. Extract the filter cake with methylene chloride several times and concentrate the filtrate to a residue. Crystallize the residues from isopropyl ether to obtain thereby the title product melting 110°-112° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.Cl[CH:7]([Cl:9])Cl.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:27])[C:25]=1[F:26])[NH:22][C:21](=[O:28])[CH2:20][CH2:19]2>O>[Cl:9][C:7]1[NH:22][C:23]2[C:18]([CH2:19][C:20]=1[CH:21]=[O:28])=[CH:17][C:16]([F:15])=[C:25]([F:26])[C:24]=2[F:27]
Reactant: O=C1CCc2cc(F)c(F)c(F)c2N1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=C(Cl)Nc2c(cc(F)c(F)c2F)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
50 cm3 of phosphoryl chloride are added in the course of 40 minutes, with stirring, at between 5° and 10° C., to a mixture of 525 cm3 of trichloromethane and 49 cm3 of dimethylformamide, the mixture is stirred for 15 minutes at this temperature and the temperature is allowed to rise to about 20° C. 46.8 g of 6,7,8-trifluoro-3,4-dihydrocarbostyril are added progressively in the course of 20 minutes, at about 20° C., with vigorous stirring, to the solution obtained. The mixture is stirred for 30 minutes at a temperature close to 20° C., heated to about 60° C. and kept at this temperature for 2 hours and a half. The reaction mixture is concentrated under reduced pressure (20 kPa) at about 50° C. The oily residue is poured into 500 g of ice, with vigorous stirring. 100 g of sodium acetate are added in small fractions in the course of 30 minutes. The suspension obtained is poured in the course of 15 minutes, with vigorous stirring, into 1 liter of water which has previously been heated to about 90° C. and the mixture is stirred for a further 15 minutes at this temperature. The insoluble matter is drained at about 90° C. and washed with 3 times 250 cm3 of water. 47.7 g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a colorless solid which decomposes at 220° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([C:33]2[N:41]3[C:36]([CH:37]=[N:38][C:39](O)=[N:40]3)=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH:21][C:39]2[N:38]=[CH:37][C:36]3=[CH:35][CH:34]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=4)[N:41]3[N:40]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(N)ccc1Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
This example was prepared by using (S)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c. 1H-NMR (CDCl3) δ 8.7 (brs, 1H), 8.6 (m, 1H), 8.4 (d, J=8.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 7.7 (t, 1H), 7.5-7.0 (m, 5H), 4.1-3.9 (m, 3H), 3.5-3.2 (m, 2H), 3.0 (s, 3H), 2.2 (m, 3H), 1.9 (m, 1H); LC/MS (ESI+): 598 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C-:13]#[N:14].[Na+]>CN1CCCC1=O.O.[Ni](Br)Br>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[C:2]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1
Reactant: [C-]#N
Reactant: O=C1CCc2c(Cl)cccc2N1
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CCC(=O)N2
Temperature: 200 °C

Procedure:
To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 1.8 g, 0.0099 mol) and nickel bromide (2.15 g, 0.0099 mol) in N-methyl-2-pyrrolidone (10 mL) was added sodium cyanide (0.97 g, 0.0198 mol) portion wise at room temperature. Reaction mixture was heated at 200° C. for 10 min under microwave irradiation. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M−1): 171.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(=O)Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (104.8 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (14.7 mg, 8%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.50 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.96 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 3.93 (s, 2H), 3.34 (s, 2H), 3.10 (br. s., 4H), 2.91 (s, 3H), 2.46 (br. s., 4H). [M+H] calc'd for C, 19; H, 22; ClN, 5; O, 372; found, 372.