Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH2:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:21]1([C:2]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH2:11][CH3:12])=[CH:4][C:3]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH2:23][CH2:22]1
Reactant: CCOc1cc(-c2ccc(F)cc2F)c(Br)cc1C=O
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1C=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 2-bromo-5-ethoxy-2′,4′-difluorobiphenyl-4-carbaldehyde (5.70 g), cyclopropylboronic acid (2.15 g), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (549 mg), tris(dibenzylideneacetone)dipalladium (0) (612 mg) and 2 M aqueous sodium carbonate solution (25.1 mL) in toluene (50 mL) was stirred at 100° C. for 2 hours under nitrogen atmosphere. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate. Activated carbon (600 mg) was added to the filtrate. The mixture was stirred for 20 minutes at room temperature. After filtration, the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.62 g).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Br>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Clc1cccc(C[Mg]Br)c1
Product: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2

Procedure:
The title compound was synthesized in two steps. Methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-chlorobenzylmagnesium bromide (0.25 M in hexanes, 25 mL, 6.3 mmol) according to General Procedure 3 to give the exocyclic olefin-containing compound (E)-methyl 6-(3-chlorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 143 mg.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(=O)C)[CH2:8][CH2:7]1)=[O:5].[ClH:20]>C(O)(=O)C>[ClH:20].[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1F)C1CCNCC1
Yield: 83 %

Procedure:
The preceding ketone (40 g, 0.15 mol) was added to a mixture of 125 ml concentrated HCl and 125 ml acetic acid and refluxed for 16 hours, cooled, and concentrated in vacuo. The white residue was triturated with hot isopropanol, filtered, washed with Et2O and dried to give 32.3 g (83%) of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride (III), m.p. 215°-216° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][NH:20][C:21]=2[C:22]#[N:23])=[CH:13][C:12]=1[F:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:30]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:30][N:20]1[C:21]([C:22]#[N:23])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[C:12]([F:29])[CH:13]=2)[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 1-L 3-neck rbf was fitted with an overhead stirrer and charged with sodium hydride (60% dispersion in mineral oil, 2.19 g, 54.6 mmol) and DMF (550 mL). Ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate (10.00 g, 45.5 mmol) was added and the mixture was left to stir at rt for 15 min. The reaction mixture was treated with (aminooxy)(diphenyl) phosphine oxide (12.74 g, 54.6 mmol) and heated to 60° C. The very thick reaction mixture gradually became a readily stirred suspension. After 1 h analysis by RP-HPLC indicated that all starting material had been consumed. The reaction was cooled to rt and diluted with 1.5 L EtOAc and aq. sodium bicarbonate. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layers were dried (sodium sulfate) and filtered through a silica plug. Trituration with ether:hexanes (1:2) gave the title compound as a yellowish powder (18.06 g, 46.5 mmol, 93.7%). 1H-NMR (DMSO-d6) 9.13 (s, 1H), 7.68 (s, 1H, 7.68 (t, J=8 Hz, 1H), 7.29 (dd, J=12, 2 Hz, 1H), 7.19 (dd, J=8 Hz, 1H), 6.67 (s, 2H), 4.14 (q, J=7 Hz, 2H), 1.50 (s, 9H), 1.18 (s, 3H); MS [M+Na]+=411.0; LCMS RT=3.48.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[N:57]=[CH:58][O:59][C:60]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[O:59][CH:58]=[N:57][C:56]=2[CH3:55])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1ncoc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncoc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methyl-1,3-oxazole-5-carbonyl chloride as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.40 (s, 1H), 8.30 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.52 (m, 2H), 3.12 (m, 1H), 2.98 (m, 4H), 2.32 (m, 2H), 2.21 (s, 3H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a 3000 mL RB flask was added (4S)-4-(phenylmethyl)-1,3-oxazolidin-2-one (100 g, 0.564 mol) in THF (1500 mL). The solution was cooled to −78° C. and n-butyl lithium (1.6 M in hexanes, 387 mL, 0.62 mol) was added dropwise. Stirring continued for 30 min. Hexanoyl chloride (74.8 g, 0.62 mol) was then added dropwise and the reaction was monitored by TLC. The reaction was quenched by addition of NH4Cl (400 mL), and extracted with DCM (2×500 mL). The product was purified by flash column eluting with ethyl acetate/petroleum ether (1:50 to 1:20) to afford the title compound (118 g, 76%). LCMS: (M+H)+: 276.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)=[O:17])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].[BH4-].[Na+].C(OCC)(=O)C>O1CCCC1CO>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[O:17])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCc2cc(NC(=O)c3ccc(-c4ccc(C=O)cc4)cc3)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCC1CCCO1
Product: CN(C)CC1CCc2cc(NC(=O)c3ccc(-c4ccc(CO)cc4)cc3)ccc2C1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
N-[6-[(N,N-Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-formyl[1,1′-biphenyl]-4-carboxamide (100 mg, 0.242 mmol) was dissolved in tetrahydrofuran-methanol (1:1) solution (2.4 ml), then sodium borohydride (18.3 mg, 0.485 mmol) was added, which was stirred for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried using anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The residue was pulverized using ether-n-hexane, to give the titled compound (86 mg) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:21])=[O:20]
Reactant: ClCc1ccccc1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNc1cc(C(=O)OCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
Bumetanide (1.15 g, 3.15 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and benzyl chloride (400 uL, 2.8 mmol) was added followed by triethylamine (480 uL). The reaction was heated to 80° C. for 12 hours, at which time TLC and LC/MS indicated the reaction was complete. The reaction was cooled to room temperature, brought up in dichloromethane and washed with water, saturated ammonium chloride and concentrated to a thick slurry. To the slurry was added water (25 mL). The resultant solids were filtered and dried in a vacuum oven at 50° C. for 12 hours to yield 1.0 g (80%) of benzyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=O)C.[CH2:40]([NH2:42])[CH3:41]>CO>[CH2:40]([NH:42][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:3])[CH3:41]
Reactant: CCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1 (Example 1(g), 5 mg) in 1 mL of methanol was added 1 mL of ethylamine (2 M in methanol). The solution was stirred at 70° C. for 30 minutes. The solvent was evaporated and the product was purified by preparative HPLC as the formic acid salt (1 mg, yellow solid). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.71 (m, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 8.24 (br, 1H), 7.69 (br, 1H), 7.42 (d, 1H), 7.27 (m, 3H), 7.17 (d, 1H), 6.67 (br, 2H), 3.50 (m, 2H), 3.25 (m, 4H), 3.03 (m, 4H), 2.92 (m, 4H), 2.55 (s, 3H), 2.22 (m, 2H), 1.27 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N7O2: 524.27 (M+H), Found: 524.3.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][OH:11].O.C(Cl)Cl.CO>CCO>[OH:11][N:10]=[C:4]([NH2:5])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: NO
Reactant: Cc1ccccc1C#N
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(N)=NO
Temperature: 70 °C
Yield: 100 %

Procedure:
A mixture of 2-methyl-benzonitrile (0.950 mL, 8 mmol), hydroxylamine 50% in water (1.6 mL, 24 mmol) and EtOH (8 mL) was heated at 70° C. for 48 h. TLC analysis (DCM/MeOH: 97/3 as eluent) indicates the completion of the reaction. The solvent was removed under reduced pressure to afford 1.2 g of N′-hydroxy-2-methylbenzamidine (Yield: 100%) as a white powder (M.P.=147-148.5° C.). which can be used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])#[N:2].CC(O)=[O:30]>C(O[Pd]OC(=O)C)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:6]=[C:7]2[C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:17]=[CH:18][C:19]2=1)(=[O:30])[NH2:2]
Reactant: CC(=O)O
Reactant: COC(=O)c1cccc(Nc2ccc(-c3cccc(OC)c3)cc2C#N)c1
Agent: CC(=O)O[Pd]OC(C)=O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(OC)c3)cc12
Temperature: 130 °C

Procedure:
A mixture of methyl 3-(3-cyano-3′-methoxybiphenyl-4-ylamino)benzoate (3.3 g, 9.21 mmol), diacetoxypalladium (5.17 g, 23.02 mmol), and AcOH (150 mL) in a pressure vessel was heated at 130° C. for 48 h. The sold was separated by filtration and washed with several times with HOAc. The filtrate was taken and the HOAc was removed under reduced pressure. The residue was dissolved in a mixture of DCM and MeOH and mixed with silica gel (12 g). After the removal of solvents, the mixture was loaded to a silica gel column and eluted with DCM containing 0 to 1.5% MeOH to afford 140 mg of methyl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylate. MS (ESI) m/z 375.2 (M+H). 1H NMR (MeOD) δ ppm 9.28 (1H, d, J=1.53 Hz), 8.18 (1H, d, J=1.53 Hz), 7.86 (1H, d, J=7.32 Hz), 7.78 (1H, d, J=7.93 Hz), 7.46 (1H, t, J=7.78 Hz), 7.32-7.41 (2H, m), 7.31 (1H, d, J=2.14 Hz), 6.88 (1H, dd, J=7.48, 1.98 Hz), 4.04 (3H, s), 3.89 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23].Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23])[CH2:29][CH3:30]
Reactant: CCn1c(-c2ccc(N)c(F)c2)c(C#N)c2ccc(OC)cc21
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A biphasic mixture of 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (74 mg, 0.24 mmol), prepared as described in example 1 Gb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][OH:57])=[CH:51][CH:50]=1>>[Cl:17][C:18]1[C:19]([O:57][CH2:56][CH2:55][C:52]2[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CCO)cc1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(CCOc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2Cl)cc1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-(4-methoxyphenyl)ethanol, the title compound was obtained as a colorless solid (0.17 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.29-7.23 (m, 3H), 6.90-6.85 (m, 2H), 4.30 (t, J=6.8 Hz, 2H), 3.72 (s, 3H), 3.01 (t, J=6.8 Hz, 2H), 2.87 (s, 6H); MS (ES−) m/z 429.2, 431.2 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1N1CCNCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1N1CCNCC1
Reaction time: 16 h
Yield: 63 %

Procedure:
2-Piperazin-1-yl-benzoic acid (1.000 g, 4.89 mmol) is suspended in 10 mL of MeOH. To this is added 5 mL of conc. H2SO4. The mixture is stirred for 16 h resulting in a white precipitate. An additional 5 mL of H2SO4 is added with an additional 10 mL of MeOH. The reaction volume is increased by an additional 200 mL of MeOH and 60 mL of H2SO4 and the mixture is stirred an additional 2 h and then heated at reflux for 12 h. The reaction volume is then reduced to approximately 175 mL and applied to an ion exchange column, eluting with 5×200 mL of 10% NH3/MeOH and then the product fractions are concentrated. The eluent is co-evaporated with toluene to remove residual water to give 0.667 g of 2-piperazin-1-yl-benzoic acid methyl ester in 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:13][CH:14]([O:24][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:15][CH3:16]
Reactant: O
Reactant: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCC(C)OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Next, S(+)-2-octanol (50 g, 0.38 mol) was dissolved in dry pyridine (150 ml), and to the solution was dropwise added under cooling, a solution of 4'-benzyloxybiphenyl-4-carboxylic chloride (112 g, 0.35 mol) dissolved in dry toluene (150 ml), followed by agitating the mixture at about 50°-60° C. for 2 hours, thereafter adding water (300 ml) and toluene (300 ml), agitating the mixture, washing the separated toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the toluene layer with anhydrous sodium sulfate and distilling off toluene to obtain 4'-benzyloxybiphenyl-4-carboxylic acid 1-methylheptyl ester (53 g), dissolving this ester (53 g, 0.13 mol) in ethanol (500 ml) and reducing it in the presence of palladium/carbon (Pd/C) 5 g) to obtain 4'-hydroxy-4-(1-methyl-heptyloxycarbonyl)biphenyl (34 g). (ii) Preparation of 4-octyloxycarbonyloxybenzoic chloride
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (18 mg, 0.45 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (142 mg, 0.40 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 0.5 hours. Ethyl 2-bromopropionate (37 μl, 0.33 mmol) was added and the mixture was stirred for 2 days, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (90 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[H-].[Na+].Br[C:10]1[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=[C:14]([Cl:16])[CH:15]=1.CN(C=O)C>C1COCC1>[Cl:16][C:14]1[CH:15]=[C:10]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=1
Reactant: Nc1ccon1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Reaction time: 0.17 h

Procedure:
To a solution of isoxazol-3-amine (25.8 mg, 0.307 mmol) in THF (0.5 mL) was added 60% NaH (12.26 mg, 0.307 mmol). The mixture was stirred for 10 min and 5A (40 mg, 0.123 mmol) was added followed by DMF (0.5 mL). The mixture was stirred overnight. The solvent was removed under a stream of nitrogen and water was added. The resulting solid was collected by filtration, rinsed with water, and dried on vacuum to give the title compound as a yellow solid.