Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:11]=1)(=[O:5])[CH3:4].[F:27][C:28]([F:44])([F:43])[C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][CH:42]=1)[CH2:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24][N:36]2[CH2:37][CH2:38][CH2:39][N:33]([CH2:32][C:31]3[CH:40]=[CH:41][CH:42]=[C:29]([C:28]([F:43])([F:44])[F:27])[CH:30]=3)[CH2:34][CH2:35]2)[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: FC(F)(F)c1cccc(CN2CCCNCC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCCN(Cc3cccc(C(F)(F)F)c3)CC2)nc(-c2ccccc2)n1

Procedure:
Sodium iodide (903 mg; 6.02 mmol) was added to a solution of chloroacetamide 6 (2.088 g; 6.00 mmol), 1-(3-trifluoromethylbenzyl)-[1,4]diazepane (7.40) (1.863 g; 7.21 mmol) and DIPEA (1.45 mL; 8.32 mmol) in 3:1 acetonitrile:THF (30 mL). After 21 h the reaction was concentrated on a rotary evaporator. EtOAc (90 mL) was added and the suspension was washed with 50% saturated NaHCO3 (25 mL), water (3×25 mL) and saturated NaCl (2×25 mL). The solution was dried (MgSO4), filtered, concentrated to an oil then purified on silica gel (340 mL), eluting with 9:1 EtOAc:methanol. Pure product was obtained as a hard white foam (3.10 g; 91%). LC (method B) tR=12.6 min; 1H NMR (200 MHz, CDCl3) δ 9.64 (s, 1H), 8.36 (m, 2H), 7.7-7.3 (m, 7H), 7.22 (s, 1H), 6.56 (brs, 1H), 5.42 (brt, J=5.8 Hz, 1H), 3.75 (s, 2H), 3.68 (m, 2H), 3.54 (m, 2H), 3.32 (s, 2H), 3.0-2.7 (m, 8H), 1.93 (m, 2H), 1.65 (s, 3H). ESIMS 570 (12) [MH+], 286 (100).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:21])C(=O)C1>C(O)(=O)C>[I:21][C:10]1[C:11]([OH:13])=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: Oc1ccnc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)ncc1I
Temperature: 50 °C
Yield: 69.4 %

Procedure:
To a solution of 2-phenylpyrimidin-4-ol (1.0 g, 5.8 mmol, 1 eq) in acetic acid (20 mL), was added NIS (1.3 g, 5.8 mmol, 1 eq), then heated at 50° C. for 1 h. The reaction solution was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2/MeOH=97/3 as eluent) to obtain 5-iodo-2-phenylpyrimidin-4-ol (1.2 g, 69.8%) as a white solid. LC-MS (m/z): 298.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.51 (m, 3H), 8.10-8.18 (m, 2H), 8.43 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].O.O.Cl[Sn]Cl>C(O)C>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1c(F)cccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1c(N)cccc1F)C(=O)OCC
Temperature: 70 °C

Procedure:
To a stirred solution of diethyl 2-(2-fluoro-6-nitrobenzyl)malonate (146-2; 2.5 g, 0.0079 mol) in ethanol (30 mL) was added SnCl2.2H2O (8.9 g, 0.0395 mol) with constant stirring. The reaction mixture was heated at 70° C. for 0.5 h to 1 h. The reaction mixture was cooled to room temperature and then filtered through CELITE bed. The filtrate was basified with saturated Na2HCO3 solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. MS (M+1): 284.1.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C([Li])CCC.Cl[C:51]([O:53][CH2:54][CH3:55])=[O:52]>C1COCC1>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([N:36]([CH3:37])[C:51](=[O:52])[O:53][CH2:54][CH3:55])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(C)C(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.163 mmol) in THF (2 mL) at −78° C. under N2 added n-butyllithium (0.203 ml, 0.325 mmol). After 10 mins, ethyl chloroformate (61.8 mg, 0.569 mmol) was added to the reaction mixture. And the reaction mixture was warmed to room temperature and stirred overnight under N2. The reaction mixture was quenched with 5 ml water extracted with 3×10 mL ethyl acetate. The organic layers were combined, washed with 2×5 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Silica gel chromatography eluted with ethyl acetate/hexane (20-100%) resulted in 38 mg (34%) of Ethyl (5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran -3-carbonyl)(methyl)carbamate (Compound 208) as a white solid. LC-MS (ES, m/z) C35H28F2N4O7S: 686. Found: 687 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4].[NH:51]1[CH2:61][CH2:60][CH:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:53][CH2:52]1>>[CH3:41][O:40][C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[C:3](=[O:4])[CH2:2][N:51]3[CH2:61][CH2:60][CH:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:53][CH2:52]3)=[O:16])=[O:24])=[CH:27][CH:28]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(=O)CCl
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(CC(=O)N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C(CC)CC)CC1
Yield: 87.9 %

Procedure:
By using 370 mg of methyl 4-(2-{4-[({2-[(3-{[(chloroacetyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate and 400 mg of ethyl isonipecotate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 380 mg of ethyl 1-(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}-2-oxoethyl)piperidine-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:4][C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([C:13]([O:15]CC)=O)[C:7]=1[C:8]([O:10]CC)=O.O.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:10])[NH:36][NH:35][C:13](=[O:15])[C:6]=2[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[N:4][C:3]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NN
Reactant: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2nc(-c3ccccc3)c(N)c3c(=O)[nH][nH]c(=O)c23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 0.251 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(p-tolylsulfonyl)pyridine were added 2 ml of hydrazine monohydrate and 2 ml of ethanol, and the mixture was stirred at 90° C. for 2 hours. After ethanol was added, the mixture was cooled. The resulting precipitate was collected by filtration and washed with ethanol. The thus obtained precipitate was suspended in 30 ml of water, and 2 ml of acetic acid was added thereto. After the mixture was heated, it was cooled. The resulting precipitate was collected by filtration, washed with water and dried to give 0.15 g of the title compound.
Reaction SMILES: [Na].[SH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.Cl[CH2:15][N:16]1[C:20](=[O:21])[CH:19]([CH2:22][CH2:23][CH3:24])[NH:18][S:17]1(=[O:26])=[O:25]>CN(C=O)C>[C:8]1([N:7]2[C:3]([S:2][CH2:15][N:16]3[C:20](=[O:21])[CH:19]([CH2:22][CH2:23][CH3:24])[NH:18][S:17]3(=[O:25])=[O:26])=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(CSc2nnnn2-c2ccccc2)C1=O
Temperature: 0 °C
Yield: 96.5 %

Procedure:
The sodium salt of 5-mercapto-l-phenyl-1H-tetrazole (0.42 g) ##STR16## was added to a solution of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (0.44 g) in DMF (10 ml), and the resulting mixture was allowed to react at 50° C. for 6 hours and then cooled. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography (35% ethyl acetate in hexane) to afford 0.69 g (96%) of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =propyl;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[N:17]=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Yield: 111.5 %

Procedure:
To a stirring solution of 4-(6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg) in a 1:1 mixture of ethanol and toluene (10 ml) was added 3-(trifluoromethyl)phenylboronic acid (277 mg), sodium carbonate (422 mg), water (500 μl) and CombiPhos-Pd6 (30.5 mg) catalyst mixture. The resulting suspension was heated at reflux for 3 hrs before being filtered through celite and concentrated in vacuo to give 4-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil (720 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](OCC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[BH4-]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH2:25][OH:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]c(CO)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (1.18 g, 3.0 mmol) was added to a solution of LiBH4 (132 mg, 6.0 mmol) in THF (10 mL) and water (0.1 mL). The mixture was allowed to stir for 16 h at 25° C. before it was quenched with water (10 mL) and slowly made acidic by addition of 1 N HCl. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl)-1H-indol-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 350.4, found 351.3 (M+1)+; retention time 2.59 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>CN(C)C1C=CN=CC=1.CO>[CH2:11]([O:10][C:9]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:13])[CH3:12]
Reactant: CCOC(=O)OCC
Reactant: NCC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CCOC(=O)NCC1CCNCC1

Procedure:
The solution of 1.70 g (9.0 mmol) of 4-(ethoxycarbonylamino-methyl)-piperidine (obtained from 4-aminomethyl-piperidine and diethyl carbonate in the presence of 4-dimethylaminopyridine) in 18 ml of methanol was treated with 9.0 ml (9.0 mmol) of 1N methanolic hydrochloric acid. After addition of 0.53 g (3.0 mmol) of 8-methoxy-2-tetralone, the mixture was stirred for a further 5 minutes. 0.20 g (3.3 mmol) of sodium cyanoborohydride was then added and the mixture was stirred for 15 hours at room temperature, followed by standing for 18 days at about +4° C.
Reaction SMILES: [N:1]1([S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][N:21]=2)=[CH:16][CH:15]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C:11](=[S:12])[NH:10][S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])[N:21]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(N=C=S)N1CCCCC1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)N1CCCCC1
Yield: 63 %

Procedure:
Part A: To a stirred solution of (piperidin-1-yl)sulfonyl isothiocyanate (54.77 g, 266 mmol) in dry dichloromethane (900 mL) in a nitrogen atmosphere is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (68.3 gram, 266 mmol). After stirring for 16 hours an additional amount of dichloromethane is added. The resulting solution is twice washed with water, dried over Na2SO4, and concentrated in vacuo. After addition of MTBE, the residue crystallizes. The crystalline material is collected and washed with MTBE to give 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (77.6 gram, 63% yield).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O.Br[C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]1([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=2)[CH2:3][CH2:2]1
Reactant: Nc1cncc(Br)c1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cncc(C2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
Cyclopropylboronic acid (360 mg), cesium carbonate (1.4 g), and Pd(PPh3)4 (166 mg) were added to a 1,4-dioxane/water (4.5 ml/0.5 ml) solution containing 5-bromopyridin-3-amine (500 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 100° C. for 5 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 30:1). A brown solid of 5-cyclopropyl pyridin-3-amine (314 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].CO[C:12]1[CH2:17][CH:16]=[C:15]([CH3:18])[CH2:14][CH:13]=1.II>O1CCCC1.ClC1C=CC=CC=1.C(O)(=O)C.CCCCCC.C(OC)(C)(C)C.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COC1=CCC(C)=CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: II
Solvent: COC(C)(C)C
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(Nc2c(Cl)cccc2Cl)cc1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of 4.35 g 2,6-dichloro-aniline in 4 ml of tetrahydrofuran and 35 ml of chlorobenzene is cooled down to −40 to −45° C. At this temperature, 5.09 g of titanium-tetrachloride is added to the solution, followed by the addition of 5.0 g of 1-Methoxy-4-methylcyclohexa-1,4-diene. The reaction mixture is allowed to warm up to approximately −35° C. and stirred for 2 hours at this temperature. A solution of 10.18 g of iodine in 20 ml of tetrahydrofuran and 2.3 ml of acetic acid is then added dropwise to the reaction mixture and the temperature was allowed to warm up to 0° C. The mixture was stirred for 1 hour at 0° C. and 16 hours at 25° C. Then 3.4 g of iodine is added to the reaction mixture and stirring is continued for additional 24 hours at 25° C. The reaction is finally quenched by pouring the reaction mixture onto a mixture of 250 ml of aqueous Sodium bisulfite (38-40%) and 400 ml of saturated aqueous sodium carbonate. The water phase is extracted with ethyl acetate (1×200 ml and 2×100 ml), the ethyl acetate phases are unified and washed with 100 ml of water. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 11.44 g of a dark slurry. The slurry was dissolved in hexane/t-butyl-methylether and the solution was filtered over silica gel to obtain, after evaporation of the solvent, 5.75 g of erode product. The product can be used directly in the next step. Alternatively, h can be purified e.g. by column chromatography on silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield pure N-(2′,6′-Dichlorophenyl)-4-methylaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[N:8][N:7]=1)=[O:5])[CH3:2].[Na].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: COc1ccc(CBr)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium tetrazole-5-carboxylic acid ethyl ester (2 g, 12.19 mmol) in DMF (8 mL) is added 4-methoxybenzyl bromide (3.68 g, 18.28 mmol) followed by the addition of triethylamine (5.10 mL). The resulting mixture is stirred at room temperature overnight then ice/water is added. The mixture is extracted with EtOAc and the combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography to afford 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid ethyl ester; HPLC Retention time 1.37 minutes (condition C): MS 263.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:13][C:14]([O:16]C)=O)[C:6]2=[N:11]O.[H][H]>CO.C(O)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]1[CH2:13][C:14](=[O:16])[NH:11][CH:6]12
Reactant: COC(=O)CC1Cc2c(Cl)cccc2C1=NO
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CC2Cc3c(Cl)cccc3C2N1
Yield: 40.7 %

Procedure:
Methyl 4-chloro-1-hydroxyimino-2,3-dihydro-inden-2-acetate (15 g) is hydrogenated at 40 atm of hydrogen in 200 ml of methanol plus 50 ml of acetic acid in the presence of 1.5 g of platinum oxide catalyst at 30°-50° C. for 7 hours. The catalyst is then filtered off, and the filtrate is concentrated. The residual oil is extracted with chloroform. The extract is washed with aqueous potassium carbonate solution, then with water and dried over sodium sulfate, and the solvent is distilled off. The residue is heated on an oil bath at 110°-120° C. for 2 hours. After cooling, ether is added, and the precipitated crystals are collected by filtration and recrystallized from ether to give 5 g of 5-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one, melting at 186°-187° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[NH2:18].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(OCC)(=O)C>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[NH:18][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccnc2ccc(C(F)(F)F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A rapidly stirred mixture of ethyl acetate and saturated aqueous sodium bicarbonate containing commercially available 6-(trifluoromethyl)quinolin-4-amine (558 mg, 2.63 mmol) was cooled to 0° C. and treated dropwise with benzyl chloroformate (1.10 mL, 3.29 mmol). After stirring overnight warming to room temperature, the aqueous layer was removed and the organic layer concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, 0-20% MeOH/Ethyl acetate) yielded the product.
Reaction SMILES: Br[C:2]1[C:3]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][N:4]=[C:3]([C:14]([NH:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[C:2]=2[CH:22]2[CH2:24][CH2:23]2)=[CH:8][CH:9]=1
Reactant: OB(O)C1CC1
Reactant: O=C(NC1CCCC1)c1noc(-c2ccc(Cl)cc2)c1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NC1CCCC1)c1noc(-c2ccc(Cl)cc2)c1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-5-(4-chlorophenyl)-N-cyclopentylisoxazole-3-carboxamide (40 mg, 0.11 mmol), cyclopropylboronic acid (22 mg, 0.26 mmol), and tricyclohexylphosphine (6 mg, 0.02 mmol) in toluene (1 mL) was degassed with Argon. 2M aqueous potassium phosphate (0.35 mL, 0.7 mmol) and palladium(II) acetate were added and the reaction heated to 100° C. for 3 hours. The volatiles were removed in vacuo and compound was purified by silica gel chromatography eluting with 2% methanol in dichloromethane to afford the title compound: (6.8 mg, 0.02 mmol). MS (ESI) m/z (M+H+): 331.2