Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24](OCC)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:39]3[CH2:38][CH2:37][N:36]([CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:41][CH2:40]3)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(C4CCN(C)CC4)CC3)o2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using Ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-(1-methylpiperidin-4-yl)piperazine (26 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][C:24]#[N:25].[NH2:26][OH:27]>CS(C)=O>[OH:27][NH:26][C:24](=[NH:25])[CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: NO
Reactant: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CS(C)=O
Product: N=C(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanenitrile (2.00 g, 6.0 mmol) in dimethyl sulfoxide (15.0 mL) was added hydroxylamine (50% wt solution in water, 1.6 mL, 24 mmol). The reaction was stirred at ambient temperature for 16 h, then the product was precipitated upon addition of water/ethanol (3:1, 100 mL). The solvent was decanted and the remaining solid was triturated in distilled water (75 mL). The solid was filtered and air-dried to afford N-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanimidamide as a colorless solid (2.00 g, 91%): MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:54][S:55]([C:58]1[CH:63]=[C:62]([C@@H:64]([NH2:67])[CH2:65][CH3:66])[CH:61]=[CH:60][N:59]=1)(=[O:57])=[O:56].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:54][S:55]([C:58]1[CH:63]=[C:62]([C@@H:64]([NH:67][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:65][CH3:66])[CH:61]=[CH:60][N:59]=1)(=[O:57])=[O:56]
Reactant: CC[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1.08 g, 4.20 mmol) and DIPEA (2.19 ml, 12.6 mmol) in DMF (20 mL) was added HATU (3.19 g, 8.39 mmol). After 30 minutes, a solution of (S)-1-(2-methanesulfonyl-pyridin-4-yl)-propylamine hydrochloride salt (0.90 g, 4.2 mmol) in DCM (1 mL) was added, and the reaction mixture became homogeneous. After 16 hours, the mixture was poured into saturated aqueous NaHCO3, and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The crude material was twice purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes to afford a yellow solid. The solid was dissolved in a minimal amount of dichloromethane and diluted with hexanes, and the collected by filtration washing with diethyl ether to afford the title compound as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35]([Cl:39])=[CH:34][CH:33]=2>>[Cl:39][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=1)[C:30]([CH3:29])=[CH:38]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: Cc1cc2cc(Cl)ccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-methyl-5-chloroindole, the title compound was isolated as a yellow solid in 71% yield (95% purity by HPLC).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-])=[O:21])=[CH:18][CH:17]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O1CCCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:23][CH:24]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
A suspension of 1.40 g (36.8 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was stirred at 0° C. A solution of 13.0 g (49.0 mmol) of 4-(tert-butoxycarbonylaminomethyl)benzoate in 50 ml of tetrahydrofuran was dropwise added slowly to the suspension. After completion of the dropwise addition, the solution was heated to reflux for 2 hours and then cooled to 0° C. After 20 ml of 50% tetrahydrofuran was dropwise added to the reaction mixture, 100 ml of ethyl acetate was added thereto. Insoluble matters were filtered off and the resulting filtrate was concentrated under reduced pressure. The concentrate was isolated and purified by silica gel column chromatography to obtain 8.80 g (75.7%) of 4-(tert-butoxycarbonylaminomethyl)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C([OH:20])C.[OH-].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]23[O:20][CH:8]2[C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][CH2:12]3)=[CH:16][CH:17]=1
Reactant: CCO
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC2(Cc3ccc(Cl)cc3)OC2C1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1726 g (6.945 mol) crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one obtained as described in (b) above and ethanol (8630 ml) were charged into a 20 liter reactor and warmed to 40° C. to give a clear pale orange solution. The reaction mixture was then cooled to 18° C. and 20% (w/v) sodium hydroxide (650 ml) was added slowly with cooling (ice/water) to maintain this temperature. Keeping the reaction mixture at a temperature between 11° and 20° C., 30% (w/v) aqueous hydrogen peroxide (794 ml, 7 mol) was added over a period of 1 hour and the mixture was then stirred overnight. Water (16 liters) was then added with ice cooling and the reaction mixture stirred for 15 minutes. Centrifugation followed by washing with water (4×21/2 liters) yielded an off-white solid which was then air dried to give 1634 g 1-(4-chlorobenzyl)-1,2-epoxy-4,4-dimethylcyclohexan-3-one, m.pt. 69°-70° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[CH:5][C:4]=1F)#[N:2].[CH:13]1([OH:17])[CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[C:4]([O:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:6]([O:10][CH3:11])=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: OC1CCC1
Reactant: COc1cc(F)c(C#N)c(F)c1
Product: COc1cc(F)c(C#N)c(OC2CCC2)c1
Yield: 92 %

Procedure:
The subtitle compound was prepared from 4-cyano-3,5-difluoroanisole and cyclobutanol following the procedure described in Example 14(a). The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v) to give the subtitle compound as a white solid (92%). Rf 0.26 (dichloromethane:hexane 1:2, v/v). MS m/z 239 (MNH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.ClNC1C=CC(C(F)(F)F)=CN=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: FC(F)(F)c1ccc(NCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 208.2 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine prepared in the same manner as in step (1) of Example 1, 10.1 g (0.043 mol) of trichloroisocyanuric acid and 150 g of toluene were added, and the reaction was conducted at 110° C. for 3 hours under heating with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of a 25% sodium hydroxide aqueous solution was added thereto and stirred. An aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were further separated. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 17.6 g 2-amino-3-chloro- 5-trifluoromethylpyridine (purity as measured by liquid chromatography: 95%, yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)cc2)N1
Reaction time: 22 h
Yield: 78.5 %

Procedure:
To a stirred solution of racemic tryptophan methyl ester (3 g ) and 4-hydroxybenzaldehyde (1.84 g) in anhydrous dichloromethane (50 mL) cooled at 0° C. was added dropwise trifluoroacetic acid (1.27 mL) and the solution was allowed to react at ambient temperature. After 22 hours, the solution was washed with a saturated solution of NaHCO3, then with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with ethyl acetate to give the title compound (3.48 g) as an off-white solid m.p.:233-235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([OH:29])[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][NH:22][C:21]2=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:21]2=[O:28])[OH:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC2CC1CC2(O)c1ccc2nc[nH]c(=O)c2c1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2ccc(C3(O)CC4CC3CN4C(=O)OCc3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a mixture of 12 (10 g, 25.6 mmol) in dimethylforamide (100 mL) was added BrCH2CO2CH2CH3 (5.55 g, 33.21 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched by water and extracted with ethyl acetate. The combined organic layer was washed by water for 5 times and dried over sodium sulfate, and then concentrated in vacuo to give the product 13 (9.7 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C@@H:11]([CH3:14])[CH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[OH:13][CH2:12][C@@H:11]([CH3:14])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[C@H](Cl)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CO)Oc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
Under argon, 785 mg (6.43 mmol) of 4-hydroxybenzaldehyde and 759 mg (8.04 mmol) of (S)-(+)-2-chloro-1-propanol were initially charged in 15.7 ml of DMF. 2.04 g (19.3 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. for 20 h. The reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])=[N:17][C:4]=2[CH:3]=1.[CH3:35][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)([OH:19])[CH3:35])=[N:17][C:4]=2[CH:3]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(=O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanone (618 mg, 1.24 mmol) in THF (10 mL) was added methyl magnesium bromide (3 M in diethyl ether, 0.82 mL, 2.46 mmol) at −78° C., and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with aqueous saturated NH4Cl solution (40 mL) and extracted with ethyl acetate (2×35 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded (1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol. MS APCl calcd. for C26H26Cl2FN5O [M+H]+ 514. found 514.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[C:12](OCC)(=O)[CH2:13][C:14]([O:16]CC)=[O:15]>>[N+:1]([C:4]1[C:5]2[N:11]=[C:12]([CH2:13][C:14]([OH:16])=[O:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(O)Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 160 °C

Procedure:
3-Nitro-benzene-1,2-diamine (5.0 g) was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 48 h. After cooling to rt, flash chromatography of the crude reaction gave (4-nitro-1H-benzoimidazol-2-yl)-acetic acid (4.50 g). MS found: (M+H)+=250.0
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methyl-biphenyl-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:2]([N:1]=[C:15]=[S:16])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1N1CCOCC1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 4-(2-amino-4-chlorophenyl)morpholine (8.5 g) with thiophosgene (4.6 ml) in dioxan (25 ml) and water (100 ml) for 30 minutes at 0° C. and for 3 hours at room temperature gave 5-chloro-2-morpholinophenyl isothiocyanate as a pale yellow solid (m.p. 86°-87° C.).
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.NCC([OH:35])C>>[OH:35][CH2:9][CH:10]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH3:11]
Reactant: CC(O)CN
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-amino-2-propanol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 317 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, s) 10.29 (1H, s) 8.01 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.27 Hz) 7.69 (1H, d, J=8.00 Hz) 7.46 (1H, d, J=5.27 Hz) 7.27-7.33 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.51, 1.95 Hz) 4.71 (1H, t, J=5.76 Hz) 3.97-4.09 (1H, m) 3.27-3.48 (2H, m) 1.09 (3H, d, J=6.64 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([OH:7])=O.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Br:20][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:32])=[O:31])=[O:7]
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 68.7 %

Procedure:
3,5-Dibromo-4-(3-bromobenzyloxy)benzoic acid (0.13 mmol) was coupled with 4-nitrobenzenesulphonamide (0.64 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 58 mg (69%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-4-nitrobenzene-sulphonamide.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:4][CH:5]=2)=[O:10])=[CH:13][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1
Solvent: CS(C)=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide was dissolved in 1 mL of DMSO and stirred for 1 h with N-methylpiperazine. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridine-3-carboxamide as a pure product. MS (Q1) 422.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[CH:26]12[CH2:33][CH:30]([CH2:31][CH2:32]1)[C:29](=[O:34])[CH2:28][C:27]2=O.C(N(CC)CC)C.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:19])([F:18])[C:14]([F:16])([F:15])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:27]1[CH:26]2[CH2:33][CH:30]([C:29](=[O:34])[CH:28]=1)[CH2:31][CH2:32]2)=[O:5]
Reactant: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)O)c1C
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
235 mg (0.783 mmol) of 2-methyl-3-(methylthio)-4-(pentafluoroethyl)benzoic acid were introduced into 20 ml of dry dichloromethane and admixed in succession with 129 mg (1.02 mmol) of oxalyl chloride and also with two drops of N,N-dimethyl-formamide. After the end of evolution of gas, the mixture was heated under reflux for another 10 minutes. Then, the contents were cooled and concentrated on a rotary evaporator. The residue was taken up in 20 ml of dry dichloromethane and admixed with 119 mg (0.861 mmol) of bicyclo[3.2.1]octane-2,4-dione and a catalytic amount of DMAP. Then 158 mg (1.57 mmol) of triethylamine were added dropwise. The mixture was stirred at RT for 16 hours. For working up, 3 ml of 1N hydrochloric acid were added. Following phase separation, the organic phase was freed from the solvent and the residue, finally, was purified by chromatography. This gave 280 mg of product with a purity of 90% by weight.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH3:43])[S:31]([C:34]1[S:35][C:36]([Cl:42])=[C:37]([N+:39]([O-])=O)[CH:38]=1)(=[O:33])=[O:32]>>[Cl:42][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[N:30]([CH2:29][CH2:28][OH:27])[CH3:43])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(CCO)S(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.21) according to general procedure II.