Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.O>CN(C)C=O>[CH3:21][C:22]1[N:26]([CH2:5][CH:6]2[C:18](=[O:19])[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH3:20])[C:9]=3[CH2:8][CH2:7]2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 6 h
Yield: 97 %

Procedure:
3-[(Dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (10 g, 34 mmol) and 2-methylimidazole (16.8 g, 205 mmol, 6.0 eq.) were suspended in mixture of water (75 ml) and dimethyl formamide (37.5 ml). The reaction mixture was heated to reflux (102–103° C.) and stirred for a further 6 hours at this temperature. The reaction mixture was cooled to 5–10° C. and stirred for half an hour at this temperature. The precipitated crude ondansetron base was filtered and washed with cold water (3×90 ml) and dried under vacuum at 60° C. to give ondansetron base (9.68 g, 96.4% yield) in 98.9% HPLC purity.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.O>CN(C=O)C>[CH2:14]([C:6]1[N:7]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:2])=[O:16])[CH3:15]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide ((91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]([OH:16])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([CH:30]=[CH2:31])[CH:23]=[CH:22]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24](/[CH:30]=[CH:31]/[C:2]1[CH:3]=[CH:4][C:5]3[O:15][CH2:14][C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:8]4[CH:7]([OH:16])[C:6]=3[CH:17]=1)[CH:23]=[CH:22]2
Reactant: OC1c2cc(Br)ccc2OCc2ncccc21
Reactant: C=Cc1ccc2cc(F)c(F)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1c2cc(/C=C/c3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.37 g (1.26 mmol) of the bromo derivative of step 3 are mixed with 0.27 g (1.41 mmol) of the vinyl derivative of step 4, 8.5 mg (0.0378 mmol) of palladium acetate and 36.2 mg (0.118 mmol) of tri(o-tolyl)phosphine in 2.5 ml of DMF. The solution is degassed and cooled with an ice bath. In a nitrogen atmosphere it is dropped inside a solution of 0.27 ml (0.196 g; 1.937 mmol) of N,N,N-triethylamine in 1.2 ml DMF. The whole is stirred at 100° C. for 1 hr. Once at room temperature, 4 ml of water are dropped inside and the solid is filtered, washed with water and dried. The yield is 0.5 g (98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]([C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=CCCC(=O)Cl
Reactant: CCOC(=O)CCNCC(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N(CCC(=O)OCC)CC(=O)OCC
Reaction time: 18 h

Procedure:
To the product of Step A, 1-a, (5.10 g, 25.1 mmol) in CH2Cl2 (50 mL) was added pent-4-enoyl chloride (2.83 mL, 25.1 mmol, 98% purity) and NEt3 (4.20 mL, 30.1 mmol) at 5° C. The reaction stirred about 18 hours and was then diluted with CH2Cl2, washed with aq Na2CO3 (2 M) and brine, dried (Na2SO4), filtered and concentrated to afford the product, 1-b.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([NH:23][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (50 mmol), Et3N (100 mmol) and DMF (80 mL) was added dropwise a solution of n-butylamine (51 mmol) in DMF (20 mL) at rt, and the mixture was stirred at rt for 5 h. The reaction was quenched by cold H2O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
Add (R)-2-methylpropane-2-sulfinamide (40.5 g, 0.33 mol) portionwise to a solution of 4-bromobenzaldehyde (65.57 g, 0.35 mol) in toluene (283 mL). Stir the mixture at ambient temperature for 15 minutes, and then add sodium hydroxide (1.34 g, 0.33 mol). Stir the suspension at ambient temperature for 12 hours. Add sodium sulphate (16 g) and Celite® (16 g), and stir the suspension for 15 minutes. Then filter and concentrate the filtrate under vacuum. Purify the residue by silica gel chromatography eluting with hexane/ethyl acetate (100% to 70% hexane) to afford the title compound as a white solid (85.5 g, 88% yield). MS (m/z): 288 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].[OH-].[Na+].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C>CCOC(C)=O>[NH2:22][C:21]1[N:10]([C:4]2[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])[N:11]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnn(-c2c(Cl)cccc2Cl)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
(2,6-Dichlorophenyl)hydrazine hydrochloride (5 g, 23.42 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (40 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in methanol (50 mL) under nitrogen at −5° C. 2-(Ethoxymethylene)malononitrile (2.86 g, 23.42 mmol) added portionwise over 5 mins and the mixture stirred at 0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (5.60 g, 94%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.47 (2H, s), 7.43-7.47 (1H, m), 7.51-7.53 (2H, m), 7.73 (1H, s); m/z (ES+) (M+H)+=253; HPLC tR=1.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10]([OH:13])(=[O:12])=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH-:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1>O1CCCC1.Cl>[ClH:1].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:10]([C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH3:9])(=[O:12])=[O:13])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: COc1ccc([NH-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1c(S(=O)(=O)O)sc2ccc(Cl)cc12
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCNCC1

Procedure:
A stirred suspension of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid(4-methoxy-3-(4-tert-butoxycarbonylpiperazin-1-yl)phenylamide (D10) (193 g) in tetrahydrofuran (820 ml) and concentrated hydrochloric acid (180 ml) was heated at reflux for 1.75 h after which time a solution was obtained. The solution was concentrated and the residue dissolved in hot ethanol (600 ml). Upon cooling, a solid precipitated which was filtered and recrystallised (ethanol/water 1:1) to give the title compound (E83) as a white solid, m.p. 276-280° C. (dec.) (142 g, 83%). δH (250 MHz, D6-dmso) 2.29 (3H, s), 2.90 (4H, br s), 3.01 (4H, br s), 3.55 (3H, s), 6.54-6.71 (3H, m), 7.42 (1H, d, J8.8 Hz), 7.85 (1H, s), 7.93 (1H, d, J8.8 Hz), 9.03 (2H, br s), 10.3 (1H, br s). MH+ 452.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(c1c(Cl)cccc1Cl)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(Cl)cccc2Cl)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (403 mg), EDCI (121 mg) and HOBt (135 mg) in DMF (8 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue crystallized from EtOAc to give 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=238-240° C.; MS (m/z) 439 (M−1); 1H NMR DMSO-d6, 400 MHz) δ 10.49 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=7.83 Hz, 1H), 8.24 (d, J=7.58 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.67 (t, 1H), 7.59 (s, 1H), 7.53 (d, J=8.08 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH:10]([CH2:13][OH:14])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:14][CH2:13][CH:10]2[CH2:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[O:11]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc2c1OC(CO)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc([N+](=O)[O-])c3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol (3.14 g, 16.09 mol) in dichloromethane (100 mL) was added diisopropylethyl amine (4.16 g, 32.18 mmol), N,N-dimethylaminopyridine (0.39 g, 3.2 mmol), and p-toluenesulfonyl chloride (4.6 g, 24.13 mmol) the reaction was allowed to stir at room temperature for 12 h. The reaction was diluted with dichloromethane (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, dichloromethane: hexanes 3:10) afforded 5.2 g (94%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as off-white solid. mp 129-131° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH:13]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:24]
Reactant: O=C(C=Cc1ccc2ccccc2c1)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2ccccc2c1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1,3-di(2-naphthalenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(1,3-di(2-naphthalenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ncc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ncc(CCl)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-yl]-methanol (560 mg, 2.78 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.50 mL, 3.60 mmol) followed by DMAP (34 mg, 0.28 mmol) and Ms-Cl (0.28 mL, 3.51 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil. LC-MS-conditions 01: tR=0.81 min; [M+H]+=219.89.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C([Li])CCC.CCCCCC.CN(C)[CH:36]=[O:37]>C1COCC1>[F:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([CH:36]=[O:37])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of tert-butyl 4-(3-bromo-5-fluorophenoxy)piperidine-1-carboxylate (0.666 g, 1.78 mmol) in THF (9.0 mL) at −78° C. was added 2.5M n-butyllithium in hexane (0.78 mL, 2.0 mmol). The solution was stirred at same temperature for 30 minutes, then N,N-dimethylformamide (1.4 mL, 18 mmol) was added to reaction flask. The reaction solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was diluted with methanol and purified with prep-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product as an oil (75 mg, 13%). LCMS (M+H-100)+: 224.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:46][CH:47]1[CH2:51][CH2:50][O:49][CH2:48]1.[Cl-].[Na+]>C1COCC1>[O:49]1[CH2:50][CH2:51][CH:47]([NH:46][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:23])[CH2:48]1
Reactant: NC1CCOC1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.29 mmol) in THF (10 mL) was added 1-hydroxybenzotriazole hydrate (45.0 mg, 0.29 mmol), N-ethyldiisopropylamine (126 μL, 0.76 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (56.3 mg, 0.29 mmol) and rac-3-aminotetrahydrofuran (25.1 mg, 0.29 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (60 mg, 50%) as a white solid. MS: m/e=415.1 [M−H]−.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:24][NH:25][CH3:26]>C(O)C.C(O)(=O)C>[CH3:24][N:25]([CH2:2][CH2:1][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:13]2)=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:26]
Reactant: CNC
Reactant: C=CS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Temperature: 25 °C

Procedure:
6.9 g of 1-(p-vinylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline are stirred in 5.5 g of a 33% solution of dimethylamine in ethanol and 15 ml of ethanol. The solution is heated gradually over one hour to 78° C. and stirring is continued until the starting material is dissolved and a concentrated sample is soluble in dilute acetic acid. The solution is allowed to cool to room temperature, whereupon a dense precipitate of the reaction product forms. This precipitate is collected by suction filtration, washed with ethanol and dried, affording 6.7 g of 1-(p-dimethylaminoethylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline (formula 103).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:34][CH3:35])[N:12]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:34][CH3:35])[N:12]=1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
1,1-Dimethylethyl 4-[2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl sulfamoyl]piperazine-1-carboxylate (the product of step i) (0.36 g) and trifluoroacetic acid (1 mL) in dichloromethane (4 mL) were stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene (3×). The residual pale yellow solid was triturated with EtOAc, filtered and dried at 40° C. under high vacuum to give the title compound as a cream solid. Yield: 0.24 g.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1>>[NH2:26][C:24]1[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=[C:16]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:8])[CH2:14][CH2:13]2)[N:25]=1
Reactant: O=C(C1CCCCC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CCCCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(Cyclohexylcarbonyl)piperazine (5.9 g., 0.03 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (7.2 g., 0.03 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(cyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 223°-225° C., resolidifying and remelting at 248.0°-250.0° C. (corr.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([O:26]CC)=O)[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:30][NH2:31]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:31][CH3:30])=[O:26])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 17 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and methylamine (0.11 mL of a 8M solution in ethanol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-N-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 17% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.97 (br s, 1 H), 8.58 (s, 1 H), 7.46 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.32 (m, 2 H), 4.13 (s, 2 H), 3.49 (m, 2 H), 3.21 (m, 1 H), 3.01 (d, J=4.8 Hz, 3 H), 1.83 (m, 2 H); HRMS m/z calcd for C20H21N3O4F: 386.1516. Found: 386.1517.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([N:13]1[CH2:12][CH2:11][CH:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]3[N:25]=[CH:24][C:23]4[CH2:22][CH2:21][C:20]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=5[C:18]=4[N:17]=3)[CH:4]=2)[CH2:15][CH2:14]1)=[O:45])([CH3:42])[CH3:41]
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(C(=O)NC(C)C)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4, 5-h]quinazolin-2-yl]-acetamide are suspended in 1 mL acetonitrile and combined successively with 17 μL triethylamine and 22 μM isopropyl isocyanate. The yellow suspension is stirred for three hours at ambient temperature and then washed with aqueous potassium carbonate solution. The organic phase is evaporated down and the residue is purified by RP-HPLC. Yield: 30 mg yellow solid.