Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=1)=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:23]=1>CCO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([NH:24][C:25]2[S:26][CH:2]=[C:3]([C:5]3[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=3)[N:27]=2)[CH:23]=1
Reactant: COc1ccc(Cl)cc1NC(N)=S
Reactant: CC(C)(C)C(=O)Nc1ncc(C(=O)CBr)s1
Solvent: CCO
Product: COc1ccc(Cl)cc1Nc1nc(-c2cnc(NC(=O)C(C)(C)C)s2)cs1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A suspension of 21z (0.73 g, 2.3 mmol) and N-(5-chloro-2-methoxyphenyl)thiourea (0.73 g, 2.53 mmol) in EtOH (25 mL) was refuxed for 30 min. Upon cooling, the product was collected by filtration and washed with cold ethanol to yield 22z as a pale yellow solid (0.40 g, 84%). Mp decomposition at 216° C. 1H NMR (600 MHz, DMSO-d6): δ 11.86 (br s, 1H) 9.93 (br s, 1H), 8.64 (d, J=2.4 Hz, 1H), 7.83 (s, 1H), 7.18 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.98 (dd, J=8.4 Hz, 2.4 Hz, 1H), 3.86 (s, 3H), 1.25 (s, 9H). 13C NMR (150 MHz, DMSO-d6): δ 176.7, 162.1, 158.9, 146.6, 140.2, 136.4, 130.5, 124.7, 124.2, 121.3, 117.3, 112.1, 91.0, 56.1, 38.8, 26.6. HRMS m/z (ESI) calcd. for C18H19ClN4O2S2 (M+H)+ 423.0711. Found 423.0713.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40][NH2:41]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:41][CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=4[CH3:37])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3C)c(C)c1)C2

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 2-methylbenzylamine, m.p. 128-130° C. MS [(+)ESI, m/z]: 538 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>C1(C)C=CC=CC=1>[Cl-:14].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C

Procedure:
4-Benzyloxybenzyl chloride (1 g, 0.0043 mol) and triphenyl phosphine (1.127 g, 1 equivalent) in anhydrous toluene (20 mL) were refluxed under nitrogen for ˜8–10 hours. A white precipitate appeared in the reaction mixture. The reaction mixture was then cooled to room temperature and ether (100 mL) was added. The precipitated phosphonium salt was collected by filtration, rinsed with ether and air dried. Yield=0.55 g (25%). MALDI-TOF MS 459.51 obs. (459.54 calc.).
Reaction SMILES: [Li+].[OH-].[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>C1COCC1.CO>[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[C:11]1=[O:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nccn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nccn(Cc2ccccc2)c1=O
Yield: 81.6 %

Procedure:
LiOH (0.82 mL, 0.82 mmol, 1.0 M in H2O) was added to a solution of methyl 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.41 mmol) in a mixture of THF (4.5 mL) and MeOH (1.5 mL) at room temperature for 4 hours. The reaction mixture was acidified to pH 1 with aq. 1N HCl solution and treated with water (5 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to afford 77 mg (82%) of the desired product. 1H-NMR (400 MHz, CD3OD) δ 8.0 (d, 1H), 7.68 (d, 1H), 7.36-7.42 (m, 5H), 5.29 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
Route B: The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (Preparation 20). The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a pale yellow solid. δH (CD3OD): 1.08–1.19 (0.5H, m), 1.29–1.51 (1.5H, m), 1.54–1.62 (0.5H, m), 1.73–1.84 (1.5H, m), 3.06–3.36 (4H, m), 3.67–3.95 (2.5H, m), 4.03–4.10 (0.5H, m), 5.32 (1H, t), 6.97–7.04 (2H, m), 7.14 (1H, s), 7.26–7.33 (2H, m), 7.66 (1H, s), 8.55 (1H, s); m/z (ES+)=445 [M+H]+; RT=3.27 min.
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22]([OH:24])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][CH2:33]I.O>CN(C)C=O>[Cl:32][CH2:33][O:23][C:22](=[O:24])[CH2:21][NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCI
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCl

Procedure:
To a solution of N-tritylglycine (25.6 g) and triethylamine (14.0 ml) in dimethylformamide (DMF) (60 ml), a solution of chloroiodomethane (24.0 ml) in DMF (40 ml) was added dropwise while stirring, and the mixture was stirred for 3.5 hours at room temperature. Then the mixture was poured into water (400 ml), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and thereafter twice with aqueous sodium bicarbonate and again with water. The organic phase was dried and evaporated in vacuo to yield the crude ester. TLC: Rf = 0.7 (cyclohexane-ethyl acetate, 1:1), ir )CHCl3): 1765 cm-1 (ester carbonyl), nmr (CDCl3 -TMS standard): δ = 3.20 (s), 5.53 (s), 7.00-7.30 (m) ppm.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])=[C:10]([N:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)[N:9]2[N:27]=[CH:28][CH:29]=[C:8]2[N:7]=1.[CH3:30][S:31](OC)(=O)=S.Cl>ClCCl>[Cl:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])=[C:10]([N:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)[N:9]2[N:27]=[CH:28][C:29]([S:31][CH3:30])=[C:8]2[N:7]=1
Reactant: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(Cl)nc3ccnn23)CC1
Reactant: COS(C)(=O)=S
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1cnn2c(N3CCC(C)CC3)c(-c3ccc(F)cc3Cl)c(Cl)nc12
Temperature: 0 °C

Procedure:
With stirring, 1.06 g of aluminium trichloride were initially added to 1 g of 5-chloro-6-(2-chloro-4-fluorophenyl)-7-(4-methylpiperidin-1-yl)pyrazolo[2,3-a]pyrimidine, the preparation of which is described, for example, in WO 02/048151, in 50 ml of dichloromethane, and 0.99 g of methyl methylthiosulphonate was then added dropwise. After 15 h of stirring at room temperature, the mixture was poured into ice-water and hydrochloric acid was added. The organic phase was separated off, and the aqueous phase was extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried with sodium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using cyclohexane/ethyl acetate 4:1. This gave 0.65 g of an orange oil, logPs=5.73.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:6]N.[C:16]([O:20][C:21]([NH:23][C:24](C1C=CNN=1)=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].CC[N:40](C(C)C)C(C)C>CO>[C:29]([O:28][C:26]([N:25]([CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:3]([Br:2])[CH:4]=1)[C:24]([NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[NH:40])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1ccc(OCCCO)c(Br)c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)c1cc[nH]n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Compound 2 (0.438 g, 1.48 mmol) was dissolved in MeOH (7.00 mL), and successively treated with N,N′-bis-tert-butoxycarbonyl-1H-pyrazole carboxamidine (0.412 g, 1.33 mmol) and i-Pr2NEt (0.380 g, 2.95 mmol) at ambient temperature. The resulting mixture was stirred 3 h then concentrated and purified by chromatography on SiO2 (A: hexanes; B: EtOAc; 0-100% B over 19.2 min; 40 mL/min; 40 g column) to obtain the product as a white foam (0.61 g, 82%). 1H NMR (300 MHz, CDCl3) δ 8.5 (t, 1H), 7.5 (d, 1H), 7.2 (dd, 1H), 6.85 (d, 1H), 4.52 (d, 2H), 4.18 (t, 2H), 3.9 (t, 2H), 2.1 (m, 2H), 1.52 (s, 9H), 1.47 s (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(N(CC)CC)C>C1COCC1.O>[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:2][CH2:3][N:4]([CH2:8][CH2:7][OH:6])[C:5]1=[O:9])[CH3:11]
Reactant: O=C1OCCN1CCCl
Reactant: CCOCCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOCCCN1CCN(CCO)C1=O
Yield: 54.6 %

Procedure:
A mixture of 6.5 g of 3-(2-chloroethyl)oxazolidin-2-one, 4.57 g of 3-ethoxypropylamine and 10 g of triethylamine was refluxed for 10 hours, diluted with THF and water. The organic layer was worked up to give 5.13 g of 1-(3-ethoxypropyl)-3-(2-hydroxyethyl)imidazolidin-2-one, b.p. 110° C./0.5 mm. This material was methylated with 4.26 g of iodomethane and 1.13 g of NaH (60% in oil) in 60 ml of THF as mentioned under Example 22. This gave 3.9 g (71.4%) of oil, b.p. 100°-105° C./0.5 mm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1)#[N:2].[C:11](=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH2:11])[CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccnc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(C#N)ccn1

Procedure:
A mixture of 4-cyanopyridine-2-carboxaldehyde (0.916 g, 6.93 mmol), methyltriphenylphosphonium bromide (2.48 g, 6.93 mmol), potassium carbonate (1.2 g, 8.66 mmol), 1,4 dioxan (9.5 mL) and water (0.13 mL) was heated under reflux for 5 hours. The mixture was diluted with water (30 mL) and ethyl acetate (70 mL) and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2×40 mL), the organic fractions combined and dried over magnesium sulphate. After removing the solvent, the residue was purified by silica column chromatography using a Biotage cartridge and eluting with cyclohexane/ethyl acetate (7:3 v/v), then (1:1 v/v). This gave the title compound as an oil.
Reaction SMILES: CC(C1C=CC(OCC2OC2)=CC=1)(C1C=CC(OCC2OC2)=CC=1)C.C[C:27]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)(C1C=CC(O)=CC=1)C.[CH2:43]1[O:45][CH:44]1[CH2:46]Cl>>[CH2:41]1[CH:40]2[CH:39]3[O:42][CH:27]3[CH:36]1[CH:37]1[CH:46]2[CH:44]2[O:45][CH:43]2[CH2:38]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Product: C1C2OC2C2C1C1CC2C2OC12

Procedure:
Diglycidyl ether of bisphenol A available commercially under the trade designation of Epon 828,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH3:11][C:12]([S@:15](/[N:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:16])([CH3:14])[CH3:13]>C1COCC1.BrCCBr>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@H:18]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[NH:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[CH:3][C:4]=1[F:9]
Reactant: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cn1cc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(Cl)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a mixture of 4-bromo-1-chloro-2-fluorobenzene (11.7 g, 56.0 mmol) and magnesium turnings (2.1 g, 84 mmol) in THF (150 mL) at RT was added a few drops of 1,2-dibromoethane (1.1 g, 5.6 mmol). The mixture was stirred at RT for 1.5 h. After cooling to −78° C., (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (4.00 g, 18.7 mmol) was added and stirred at −78° C. for 6 h. The reaction was quenched with aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1) to afford the 2.9 g (45%) of (R)—N—((S)-(4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (48). LCMS (ESI) m/z: 344.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.FS([C:42]([F:47])([F:46])C(O)=O)(=O)=O>[Cu](I)I.C(#N)C>[F:46][CH:42]([F:47])[O:22][CH2:21][C@@:19]12[CH2:18][N:17]([S:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Agent: I[Cu]I
Solvent: CC#N
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COC(F)F)C1
Temperature: 50 °C

Procedure:
A mixture of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol (0.21 g), copper iodide (0.0080 g) and acetonitrile under argon was treated with 2-(fluorosulfonyl)difluoroacetic acid (0.062 mL), and the resulting mixture was heated at 50° C. for 30 hours. The mixture was cooled to room temperature, partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume), and then by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 7:3 by volume) to afford the title compound as a white solid (0.021 g). LCMS (Method C): 576 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([Sn](C)(C)C)[S:28][CH2:27]1>C(O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]4[S:28][CH2:27][N:26]([CH3:25])[CH:30]=4)[CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Reactant: CN1C=C([Sn](C)(C)C)SC1
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C3=CN(C)CS3)ccc2c1=O
Yield: 51.8 %

Procedure:
A mixture of 4.34 g ethyl 7-chloro-1,4-dihydro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylate, 6.55 g 3-methyl-5-trimethylstannylthiazole and 1.52 g dichloro- bis-triphenylphosphine palladium in 150 ml absolute ethanol was heated at 150° C. in a stirred stainless steel bomb for about 16 hrs. The product was isolated and chromatographed on silica gel. Elution with 1:1 ethyl acetate/hexane and 100% ethyl acetate gave 2.67 g ethyl 1,4-dihydro-1-(4-fluorophenyl)-7-(3-methyl-5-thiazolyl)-4- oxo-3-quinolinecarboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13][NH2:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CN
Reactant: CCc1cc(Br)ccc1C(=O)Cl
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C(=O)NC
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoyl chloride (1.00 g, 4.04 mmol) in CH2Cl2 (20 mL) was added methylamine (0.70 mL, 40% solution in water, 8.08 mmol). The mixture was stirred for 3 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a brown oil (0.857 g, 88%). 1H NMR (300 MHz, CDCl3): δ 1.21 (t, J=7.4 Hz, 3 H), 2.75 (q, J=7.5 Hz, 2 H), 2.97 (d, J=4.9 Hz, 3 H), 5.74 (s, 1H), 7.17 (d, J=8.1 Hz, 1 H), 7.32 (d, J=8.1 Hz, 1 H), 7.39 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)#[N:20]
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: CNC(=O)C=Cc1ccc(OCc2cccc(C#N)c2)cc1
Yield: 75 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 3-bromomethyl-benzonitrile. Yield=75%. Colorless solid. MS: m/e=293.2 (M++H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][NH:21][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=[CH:10]3)[CH2:25][CH2:24]1
Reactant: NCC1CC1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: Cc1ccc(CNc2ccc3cc(NCC4CC4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=308.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and aminomethylcyclopropane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (×3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to −20° C. (external temperature) and borane dimethyl sulfide (BH3-Me2S) complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (3×100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:43]=[CH:42][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:34][CH2:33][CH2:32][NH:31][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:42]=[CH:43][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:14][CH:15]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:30]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate (355 mg, 0.60 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as brown solid. Yield: 260 mg, 88%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>>[C:11]([CH2:13][C:14]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15])#[N:12]
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Product: N#CCC(=O)NCCc1ccc(F)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluorophenethylamine (10.6 g, 76.2 mmol) and ethyl cyanoacetate (8.09 mL, 76.2 mmol) was heated in an open flask at 100° C. for 18 hours. The mixture was cooled and the resulting solid was triturated with ethanol, filtered and dried. Recrystallization from ethanol provided off-white crystals (8.2 g, 52%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.03 (t, J=9 Hz, 2H), 6.26 (bs, 1H), 3.54 (q, J=7 Hz, 2H), 3.35 (s, 2H), 2.84 (t, J=7 Hz, 2H). Mass spec (ES−) m/z 205.2 (M−H−, 100%).