Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])[CH:17]=[C:16]2[C:11]([CH:12]=[C:13](Br)[CH2:14][NH:15]2)=[CH:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC>C1COCC1.CCCCCC>[CH2:21]([O:20][P:19]([C:9]1([P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10]1)(=[O:23])[O:24][CH2:25][CH3:26])[CH3:22]
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(Br)CNC2=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=c2cccnc2=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dihydro-3-bromo-1-pyrindine-6,6-diphosphonic acid tetraethylester (10 mmol) in THF (10 ml) cooled to -78° C. is added a solution of n-butyllithium (2.1 equiv) in hexane over 30 minutes. The reaction is kept at -78° C. for an additional 30 minutes. To this solution is added 2-iodoethanol trimethylsilyl (TMS) ether (2.5 equiv) and the reaction is allowed to warm to room temperature over 30 minutes. After standard aqueous work-up, dihydro-3-(2-hydroxyethanol, TMS ether)-1-pyrindine-6,6-diphosphonic acid tetraethyl ester is isolated and used in the subsequent reaction without purification.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>N1C=CC=CC=1>[N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(N2CCOCC2)c2cccnc12
Yield: 77.8 %

Procedure:
In a similar fashion using route 18 general procedure 26, 5-morpholin-4-yl-quinolin-8-ylamine 581 (154 mg, 0.67 mmol), 2-nitrobenzenesulfonyl chloride (148.86 mg, 0.67 mmol), and pyridine (1 ml) gave the title compound (216 mg, 78%) after purification by column chromatography with DCM/MeOH (100%-98:2 gradient) as the eluent.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].Cl>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]([CH2:11]3)[CH2:10]1)[CH2:12]2
Reactant: O=C(OCc1ccccc1)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
136 mg of 80% sodium hydride in oil are added to a solution of 8 g (16mmol) of benzyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in 100 ml of DMF. The mixture is left stirring for 1 h and 1.6 ml (16.4 mmol) of methyl bromoacetate are added. The reaction mixture is left stirring overnight, and it is then poured into ice cold water and acidified to pH 2 with concentrated HCl. The solid is filtered and recrystallized from ether. 8.52 g (95%) of the expected derivative are recovered, which derivative melts at 183° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@@H:39]1[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([C:48]2[O:52][N:51]=[C:50]([CH2:53][CH3:54])[N:49]=2)[O:41][C@@H:40]1OC(=O)C)(=[O:37])[CH3:36].C(O[C@@H]1[C@H](OC(=O)C)[C@@H](C2ON=C(CC)N=2)O[C@H]1OC(=O)C)(=O)C>>[C:35]([O:38][C@@H:39]1[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([C:48]2[O:52][N:51]=[C:50]([CH2:53][CH3:54])[N:49]=2)[O:41][C@H:40]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=2[NH:10][CH2:9][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: CCc1noc([C@H]2O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: CCc1noc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: Cl
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and a mixture of (2R,3R,4R,5S)-2,4-bis(acetoxy)-5-(3-ethyl-1,2,4-oxadiazol-5-yl)tetrahydro-3-furanyl acetate and (2S,3R,4R,5S)-2,4-bis(acetoxy)-5-(3-ethyl-1,2,4-oxadiazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([OH:35])[C@H:15]1[O:34][C@:16]1([CH3:33])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>COC(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([OH:35])[CH2:15][C@:16]([CH3:33])([OH:34])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: COc1c(C)c(C)c(OC)c(C(O)[C@H]2O[C@]2(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1c(C)c(C)c(OC)c(C(O)C[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 342 mg (0.70 mmol) of (1RS,2R,3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol in 1 ml of tert.butyl methyl ether was added dropwise at room temperature while stirring to a suspension of 51 mg (2 mmol) of lithium aluminium hydride in 10 ml of tert.butyl methyl ether and the mixture was subsequently stirred at room temperature for a further 1 hour. Then, 0.5 ml of water was added dropwise, the mixture was filtered through sodium sulphate, rinsed with ether and the filtrate was concentrated on a rotary evaporator. The thus-obtained crude produce (341 mg) was chromatographed on silica gel with toluene/ethyl acetate (2:1 parts by volume) and there were obtained 284 mg (84%) of (1RS,3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecane-1,3-diol, [α]D20 =+0.2° (c=2.16% in chloroform).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1)[CH3:31]
Reactant: CCNCC
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 48 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (27 mg, 0.06 mmol) was reacted with diethylamine (5 eq) to give the title compound (14 mg, 48%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:37][C:38]1[CH:39]=[C:40]([C:44]2[NH:48][C:47](=[O:49])[O:46][N:45]=2)[CH:41]=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]4[NH:48][C:47](=[O:49])[O:46][N:45]=4)[CH:39]=3)=[O:16])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: Nc1cccc(-c2noc(=O)[nH]2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2noc(=O)[nH]2)c1
Temperature: 0 °C

Procedure:
A 500 mL three-necked-reaction flask was charged with [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid (32.3 g, 78 mmol), DCM (150 mL) and a few drops of DMF. After cooling to 0° C., oxalyl chloride (8.9 mL, 102 mmol) was added by addition funnel and the mixture warmed to room temperature (over about 30 min). After this time the reaction mixture was concentrated to dryness, then charged with DCM (50 mL) and concentrated again. DCM (150 mL) was added and the reaction mixture cooled to 0° C. 3-(3-Amino-phenyl)-4H-[1,2,4]oxadiazol-5-one (14.6 g, 82 mmol) and DIPEA (41 mL, 235 mmol) in DCM (40 mL) were slowly added to the reaction by addition funnel. The reaction mixture was stirred at room temperature and monitored for starting material consumption (5 h). Upon completion, the reaction mixture was quenched with 2N HCl (140 mL), and washed with DCM (1×100 mL), then after phase separation the organic layer was washed with brine (1×100 mL). The organic layer was separated and dried (Na2SO4, 75 g), filtered and concentrated to yield a light yellow solid after high vacuum. The solid was crystallized from MeCN to yield the title compound as an off white solid.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:42]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[NH:44]1[C:48]([C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])=[N:47][CH:46]=[N:45]1>>[CH:52]([O:51][C:49]([C:48]1[N:44]([CH2:42][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]3=[N:34][C:33]=2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:45]=[CH:46][N:47]=1)=[O:50])([CH3:54])[CH3:53]
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: CC(C)OC(=O)c1ncn[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CC(C)OC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and isopropyl 1H-1,2,4-triazole-5-carboxylate. m/e+ 430 for C20H18Cl2N5O2 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.41 (dd, J=0.9, 1.8 Hz, 1H), 8.01 (s, 1H), 7.82 (dd, J=2.1, 6.6 Hz, 2H), 7.64 (dd, J=0.9, 9.3 Hz, 1H), 7.46 (dd, J=2.1, 6.6 Hz, 2H), 7.28 (dd, J=1.8, 9.3 Hz, 1H), 6.21 (s, 2H), 5.38 (m, 1H), 1.50 (d, J=6.0 Hz, 6H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.353, 151.649, 146.894, 144.844, 144.190, 135.015, 132.017, 130.301, 129.199, 127.410, 122.448, 121.573, 118.355, 114.495, 71.973, 44.202, 21.946 ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].CC1C=CC(C)=CC=1N.[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:6][C:20]([CH3:21])=[O:22]
Reactant: Cc1ccc(CO)cc1N
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(C)c(N)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(CO)ccc1C
Yield: 114.1 %

Procedure:
To a solution of an approximately 1:1 mixture of 3-(hydroxymethyl)-6-methylaniline, (8.05 g, 58.8 mmol) (2) and 2,5-dimethylaniline in chloroform (290 mL), was added acetic anhydride (20 mL, 206 mmol) and potassium acetate (20 g, 202 mmol). The resulting mixture was heated to its reflux temperature for 2 hours. The mixture was then concentrated and purified by a flash column chromatography (1:1 of hexane-ethyl acetate) which also removed the by-product from Example 61 to give the title compound (12.02 g, 92%). TLC Rf: 0.52 (ethyl acetate); MS (electrospray) 222 (M+1); 1H N MR (CDCl3) δ2.09 (s, 3H), 2.21 (s, 3H), 2.25 (s, 3H), 5.06 (s, 2H), 7.00 (br s, 1H, NH), 7.08 (d, 1H, J=7.6 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.81 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[CH:15][CH:16]=[C:3]12.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[C:53]([NH2:58])[CH:52]=1>O1CCCC1>[NH2:58][C:53]1[CH:52]=[C:51]([F:50])[CH:56]=[CH:55][C:54]=1[NH:57][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]1[CH:14]=[CH:15][CH:16]=[C:3]1[C:2]2=[O:1])=[O:13]
Reactant: O=C(O)c1cccc2c1-n1cccc1C2=O
Reactant: Nc1ccc(F)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(F)ccc1NC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
In a 250 ml round-bottomed flask under argon, a mixture of 620 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid obtained according to the preceding stage, 1.50 g of o-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 0.44 ml of diisopropylethylamine in 55 ml of tetrahydrofuran is stirred at ambient temperature for 1 hour. 367 mg of 4-fluoro-o-phenylenediamine are then added and the stirring is maintained for 3 days. The reaction medium is evaporated to dryness under vacuum and the residue is taken up with 15 ml of a mixture of dichloromethane and methanol (90/10 v/v). The organic phase is washed with 10 ml of a saturated solution of sodium bicarbonate, then with 3 times 5 ml of distilled water, and dried over magnesium sulphate. After evaporation to dryness under vacuum, the residue is loaded as a dry spot onto a column of silica gel (40-63 μm) and chromatographed, elution being carried out with a mixture of dichloromethane and methanol (95/5 v/v). 379 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (2-amino-4-fluorophenyl)amide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccn2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2)c1

Procedure:
A solution of 4-Methyl-2-(5-pyridin-2-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 10a (30 mg, 0.068 mmol) in MeOH (2.3 mL), platinum oxide (1.55 mg, 0.007 mmol) and 4N HCl/dioxane (19 μl) was hydrogenated at 30 psi for 3 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base; (30 mg, 99%). Calculated for C26H32F3NO2 (M+H) 447.53, Found 448.4
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.ClC([C:17]1[CH:18]=[C:19](C(C)C#N)[CH:20]=[CH:21][CH:22]=1)=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Carboxybenzyne prepared from 2-chlorobenzoic acid in the presence of a strong base is reacted with propionitrile to produce alpha-(m-carboxyphenyl)propionitrile (R. Biehl et al., J. Org. Chem., 31, 602 (1966)). The alpha-(m-carboxyphenyl)propionitrile is converted to alpha-(m-chlorocarbonylphenyl)propionitrile by using thionyl chloride. Friedel-Crafts reaction of alpha-(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride affords alpha-(m-benzoylphenyl)propionitrile. Hydrolysis of the alpha-(m-benzoylphenyl)propionitrile with methanol/sodium hydroxide gives alpha-(m-benzoylphenyl)propionic acid (see British Pat. No. 1,360,560).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:20]=[CH:19]4)[C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][C:2]1=2.C(OC([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44](O)=[O:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN1C(=O)CCC1.O.CCOC(C)=O.CC(O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:20]=[CH:19]4)[C@@H:12]([NH:14][C:44]([C@@H:40]3[CH2:41][CH2:42][CH2:43][NH:39]3)=[O:45])[CH3:13])[CH:9]=[CH:10][C:2]1=2
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NC(=O)[C@@H]1CCCN1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,28)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (19a) (102 mg, 0.24 mmol) dissolved in NMP (1 mL) was added to a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (77 mg, 0.36 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (170 μl, 0.97 mmol) in NMP (2 mL). The mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL), the organic solution was washed with brine, dried (Na2SO4), filtered and evaporated to give an oily residue. The obtained material was dissolved in EtOAc (20 mL) and treated with 5-6N HCl in 2-Propanol (5 mL), the solution was stirred at +40° C. for 1 h. Solvents was removed by evaporation. The crude material was purified by HPLC, relevant fractions was freezedried to give the title compound as a colourless solid. Yield 21 mg (16%)
Reaction SMILES: [OH-].[Na+].OO.[CH2:5]([O:8][CH2:9][CH2:10][N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21]([N:24]2[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[C:15]([CH3:33])[CH:14]=1)[CH:6]=[CH2:7].S([O-])([O-])=[O:37].[Na+].[Na+]>CO.CS(C)=O>[CH2:5]([O:8][CH2:9][CH2:10][N:11]([CH3:35])[C:12]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21]([N:24]2[CH2:25][CH2:26][C:27]([NH2:32])([C:30]([NH2:31])=[O:37])[CH2:28][CH2:29]2)(=[O:22])=[O:23])=[C:15]([CH3:33])[CH:14]=1)=[O:34])[CH:6]=[CH2:7]
Reactant: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C#N)CC2)c(C)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 N aqueous sodium hydroxide solution (1.41 ml) and 30% aqueous hydrogen peroxide (0.95 ml) were added to a solution of the resulting N-(2-allyloxy-ethyl)-4-[2-(4-amino-4-cyano-piperidine-1-sulfonyl)-ethyl]-3,N-dimethyl-benzamide in methanol (24 ml)-DMSO (1.3 ml), and the mixture was stirred at room temperature for one hour. A 10% (w/w) aqueous sodium sulfite solution (2.64 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 40 minutes. The precipitated insoluble matter was then removed by filtration. The resulting filtrate was concentrated under reduced pressure to give 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-amino-piperidine-4-carboxylic amide (2.13 g). This was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1.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=CC=CC=2N(C)C)CCCCC1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([N:36]4[CH2:37][CH2:38][CH:33]([N:32]([CH3:39])[CH3:31])[CH2:34][CH2:35]4)=[CH:25][CH:24]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12)c1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A solution of N-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-yl]-4-bromo-benzamide (1.3 g, 2.79 mmol) and 4-dimethylamino-piperidine (1.18 ml, 8.37 mmol) in dry THF (20 ml) was degassed by three vacuum-argon atmosphere cycles and treated at r.t., under argon atmosphere, with Pd2(dba)3 (50 mg), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (50 mg) and 1M LiHMDS in THF (22.3 ml, 22.3 mmol). The reaction mixture was heated to reflux and stirred for 15 min then cooled to r.t., poured into 200 ml of water and extracted with 200 ml of EtOAc. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Varian SF40-120 g) using DCM as eluant A and DCM/7N NH3 in MeOH 10:1 as eluant B. Elution with a gradient from A/B 100:0 to 0:100 over 10 CV, followed by an isocratic elution with eluant B (5 CV), gave a yellow solid that was triturated with EtOAc (15 ml), filtered, washed with EtOAc and dried affording 1.04 g (yield: 73%) of the title compound as a white solid.