Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].N1C=CC=CC=1.O=S(Cl)Cl.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])=[O:38])=[CH:33][C:32]=1[C:45]1[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH:46]=1>C(Cl)Cl>[C:41]([NH:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])=[C:32]([C:45]2[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH:46]=2)[CH:33]=1)(=[O:39])=[O:38])([CH3:44])([CH3:42])[CH3:43]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2N)CC1
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 363.2 %

Procedure:
A solution of 300 mg (0.976 mmol) of 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (as prepared in Example 48, step (a)) in toluene (8 mL) and EtOH (4 mL) was treated with 253 mg (1.07 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3.90 mL (7.81 mmol) of 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 113 mg (0.0976 mmol) of Pd(PPh3)4, and heated to 80° C. for 6 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1-4% MeOH—CH2Cl2 afforded 158 mg (48%) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide as a colorless glassy solid. A suspension of 215 mg (0.704 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) in CH2Cl2 (10 mL) was treated with 60.0 μL (0.704 mmol) of pyridine for 5 min. The mixture was then treated with 51.4 μL (0.704 mmol) of SOCl2 at RT for 30 min. A solution of 158 mg (0.0470 mmol) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide (as prepared earlier in this step) in CH2Cl2 (5 mL) was treated with the acid chloride solution and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 100.0 mg (17%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.95 (br s, 1H), 8.55 (d, 1H, J=8.8 Hz), 7.78 (dd, 1H, J=8.8, 2.4 Hz), 7.78 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 5.92 (s, 2H), 5.84-5.80 (m, 1H), 4.55 (br s, 1H), 3.68-3.62 (m, 2H), 2.32-2.24 (m, 2H), 2.14-2.08 (m, 2H), 1.63-1.56 (m, 2H), 1.23 (s, 9H), 1.11 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1ccccc1
Temperature: 21 °C
Reaction time: 8 h
Yield: 55820.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (200 mg, 0.78 mmoles) and potassium carbonate (130 mg, 0.93 mmoles) in 10 ml DMF was added dropwise benzyl bromide (0.14 ml, 1.2 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 100 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 151 grams (56% yield) of the desired 6-benzyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 148.8°-150° C.; TLC in 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ5.28 (s, 2H), 7.30-7.55 (m, 10H), 8.78 (dd, 1H, J=8.1, 1.9), 8.94 (dd, 1H, J=4.5, 1.9); 13C NMR (75 MHz, CDCl3 ) δ154.31, 151.66, 136.97, 136.84, 136.17, 134.30, 134.13, 130.02, 129.51, 129.05, 128.23, 128.07, 127.77, 122.10, 122.01,119.86, 52.04; IR (KBr) vmax 1645, 1612, 1589, 1552, 1483, 1460, 1439, 1417, 1369, 1304, 1294, 1197, 1170, 790, 744, 729, 713, 702, 692, 599 cm-1 ; mass spectrum (EI), m/e 346. Anal. (C21H15ClN2O) Calcd.: C, 72.73; H, 4.36; N, 8.08. Found: C, 72.61; H, 4.35; N, 8.14.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1C=NC=CC=1)[CH2:4][CH2:3]2.Br[C:50]1[N:51](C)[CH:52]=[CH:53][N:54]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>CO.O>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:51]([CH3:50])[CH:52]=[CH:53][N:54]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cn1ccnc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3nccn3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-1-methyl-1H-imidazole (0.015 g, 8.88 μL, 0.091 mmol) was used in place of 3-bromopyridine. Also, addition of LiOH, water and methanol were unnecessary for this example, as the ester hydrolysis occurred spontaneously during the course of the amination reaction. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 8 as a beige solid (38.1 mg, 51.5% yield) bis TFA salt. LCMS: m/e 653.4 (M+H)+, 3.88 min (method 16). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 6.86 (s, 1H), 6.83-6.79 (m, 1H), 5.28 (d, J=5.5 Hz, 1H), 4.84 (s, 1H), 4.73 (s, 1H), 4.71 (br. s., 1H), 3.98-3.82 (m, 2H), 3.58 (s, 3H), 3.25 (br. s., 1H), 2.89-2.78 (m, 1H), 2.18-2.07 (m, 3H), 2.05-1.92 (m, 3H), 1.90-1.79 (m, 1H), 1.72 (s, 4H), 1.69 (br. s., 1H), 1.62-1.54 (m, 3H), 1.53-1.47 (m, 3H), 1.46-1.34 (m, 5H), 1.28-1.20 (m, 2H), 1.18-1.12 (m, 1H), 1.11 (s, 3H), 1.09-1.03 (m, 4H), 1.01 (s, 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH3:18])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([Si:32]([CH3:35])([CH3:34])[CH3:33])C(=O)C(F)(F)F.[Br:36]N1C(=O)CCC1=O>ClCCl>[C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([O:21][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:20])=[C:14]([CH2:18][Br:36])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a suspension of 335 mg (1.00 mmole) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 279 mg of N-methyl-N-trimethylsilyltrifluoroacetamide (1.40 mmoles) were added and the mixture was stirred for 10 minutes at room temperature to obtain a clear, yellow solution. This was cooled in an ice-bath and bromination was carried out in half an hour using 253 mg of N-bromosuccinimide (1.42 mmoles) as the brominating agent to obtain a yield of 52% of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: C1(C(Cl)=O)CC1.[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[NH2:19].C1(C)C=CC=CC=1>C(O)C>[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:13]([NH:12][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])=[S:14])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)C1CC1
Agent: O=C(N=C=S)C1CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1-Cyclopropanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 52%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:35])=[CH2:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].C1C(=O)N([Br:48])C(=O)C1>ClC1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH2:35][Br:48])=[CH2:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Solvent: Clc1ccccc1
Product: C=C(CBr)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(prop-1-en-2-yl) benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AZ) (236 mg, 0.412 mmol) and NBS (110 mg, 0.618 mmol) in chlorobenzene (5 mL) was stirred at 135° C. for 2 h. The solids were filtered and washed with AcOEt. The organic portion was washed 1× with H2O and 1× with brine prior to drying over Na2SO4. Concentration and purification of the resulting residue by preparative TLC gave intermediate AZ (144 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]C1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCc2ccccc2C1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC4CCc5ccccc5C4)cc3C)c2cc1OC
Yield: 104.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1,2,3,4-tetrahydro-2-naphthalenol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10](O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([Cl:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1cc(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A suspension of 2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one (8.5 g, 27.2 mmol) in phosphorus oxychloride (50 mL) was stirred at 95° C. for 1 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with EtOAc. The resulting EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (330 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.2 g (69%) of the title compound as a white solid. LC/MS (method A): retention time=3.81 min, (M+H)+=331. 1H NMR (CDCl3, 400 MHz): δ 7.27-7.80 (m, 9H), 6.88 (s, 1H), 5.36 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:28][CH3:27])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (220 mg) of methylamine were added to pyridine (820 mg), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethanol (2 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (182 mg) as a colorless powder.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH2:7]([Cl:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O>>[ClH:16].[CH3:1][N:2]1[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][S:6][C:3]1=[N:4][NH2:5]
Reactant: O=C(CCl)c1ccccc1
Reactant: CNC(=S)NN
Product: Cl
Product: Cn1c(-c2ccccc2)csc1=NN

Procedure:
From 4-methyl-3-thiosemicarbazide and phenacyl chloride.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[CH2:16][C@H:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:29].[OH-:30]>CO.C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C@@H:13]3[CH2:14][C@H:15]([CH2:17][N:29]4[CH2:4][CH2:5][N:1]([C:6](=[O:30])[CH3:7])[CH2:2][CH2:3]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(C[C@H]2C[C@@H](c3ccc(CN4CCCC4)cc3)C2)CC1

Procedure:
Preparation as described for Example 100, General Procedure A, Step H, using the appropriated amine and the tosylate of Example 47 (cis-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester). Rf=0.24 (20% MeOH/CH2Cl2 w/0.5% NH4OH); LRMS m/z Calcd for C22H33N3O 355.5; obsd LRMS APCI (M+1) m/z 356.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:36]=[CH:35][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:16]2[CH:17]=[CH:18][C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][C@@H:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:3]4)=[CH:36][CH:35]=3)[CH:15]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](N)C2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](NS(C)(=O)=O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A solution of compound 404 (420 mg, 0.856 mmol) in DCM (2 mL) was cooled down to 0° C. and treated with neat methanesulfonyl chloride (148 mg, 1.29 mmol). The mixture was allowed to warm up to room temperature for 18 h. Cooled down to 0° C., treated with sat. NaHCO3 (1 mL), stirred for 1.5 h, diluted with DCM, washed with sat NaHCO3, dried over MgSO4 and concentrated under vacuum to afford the title compound 405 as a brown solid (430 mg, 88%) which was used without further purification
Reaction SMILES: [I-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][N:7]1[C:20]2[CH:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH:35]([O:38][CH2:39][CH2:40][OH:41])[CH2:34][CH2:33]1>C(C(C)=O)C>[ClH:3].[OH:41][CH2:40][CH2:39][O:38][CH:35]1[CH2:36][CH2:37][N:32]([CH2:4][CH2:5][CH2:6][N:7]2[C:20]3[CH:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=3[S:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:33][CH2:34]1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: OCCOC1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: Cl
Product: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 70.8 %

Procedure:
17.6 g (0.117 mole) of sodium iodide were added to a solution of 40 g (0.17 mole) of 10-(3-chloropropyl)-2-trifluoromethyl-phenothiazine in 350 ml of methyl ethyl ketone followed by the addition of first 11.8 g (0.117 mole) of triethylamine and then 17 g (0.117 mole) of 2-(4-piperidyloxy)-ethanol. The resulting solution was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness. The oil residue was stirred with a mixture of ether and dilute hydrochloric acid and the precipitate formed was recovered by vacuum filtration and crystallized from a 95% ethanol-ether mixture to obtain 40.5 g (71% yield) of 10-[3-(4-β-hydroxyethoxypiperidino) propyl]-2-trifluoromethyl-phenothiazine hydrochloride in the form of white crystals melting at 218°-219° C on a heated microscopic stage.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1>C(O)=O>[N+:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1)[N:9]([CH3:8])[CH:5]=[O:7])([O-:18])=[O:17]
Reactant: CNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN(C=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of formic acid (10 ml.) and acetic anhydride (5 ml.) was stirred at room temperature for 30 minutes. N-methyl-3,5-dinitroaniline (5.0 g.) was then added and the reaction mixture was heated on a steam bath for 10 minutes. The mixture was allowed to cool to room temperature during 40 minutes, then poured into ice-water and the precipitate was filtered off. Recrystallisation from methanol gave 3',5'-dinitro-N-methylformanilide (2.2 g.), m.p. 93°-94°C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][CH:4]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1nc(C(=O)O)co1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)co1
Yield: 75.4 %

Procedure:
In the same manner as in Example 259 and using 2-methyl-1,3-oxazole-4-carboxylic acid (77 mg, 0.60 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (150 mg, 74%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:39]([O:42]C(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[C:39]([OH:42])(=[O:41])[CH3:40].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])=[CH:38][CH:37]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(Oc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)cc1
Product: CC(=O)O
Temperature: 25 °C

Procedure:
Cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.051 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), acetic anhydride (0.010 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for twenty hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]acetamide acetate (0.046 g, 0.0000749 mol) as a white solid.