Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH:13]=[CH:12][C:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: C=CC(=O)N1CCCCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C=CC(=O)N2CCCCC2)cc1
Yield: 97.5 %

Procedure:
The acid chloride of the formula (500) and the corresponding free acid are novel and can be prepared as follows: 20.12 g (0.1 mol) of 4-bromobenzoic acid, 17.38 g (125 mmols) of acrylic acid piperidide, 25.28 g (250 mmols) of triethylamine, 0.224 g (1 mmol) of palladium acetate and 1.216 g (4 mmols) of tri-o-tolylphosphine are stirred at 115° C. for 15 minutes. The mixture is stirred with 300 ml of 2N hydrochloric acid and the crude product is filtered off. It is dissolved in 200 ml of 2N sodium hydroxide solution and the solution is filtered. 26 ml of 10N hydrochloric acid are added to the filtrate. The precipitate is filtered off, washed with water and dried. 25.27 g (98% of theory) of 4-carboxycinnamic acid piperidide are obtained in the form of white crystals; melting point 257.1° C.
Reaction SMILES: Cl[C:2](=[C:5]1[C:10](=O)[CH2:9][C@H:8]2[C@@H:6]1[C:7]2([CH3:13])[CH3:12])[CH2:3][CH3:4].C([O:16][C:17](=[O:20])[CH2:18][SH:19])C>C1COCC1.C(O)C.CC(=O)OCC>[CH2:3]([C:2]1[S:19][C:18]([C:17]([OH:20])=[O:16])=[C:10]2[C:5]=1[CH:6]1[C:7]([CH3:13])([CH3:12])[CH:8]1[CH2:9]2)[CH3:4]
Reactant: CCC(Cl)=C1C(=O)C[C@H]2[C@@H]1C2(C)C
Reactant: CCOC(=O)CS
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1sc(C(=O)O)c2c1C1C(C2)C1(C)C
Temperature: 30 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
To a solution of (1R,5S)-2-[1-chloro-propylidene]-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (11.0 g, 55.4 mmol) in THF (40 mL) a solution of ethyl-2-mercaptoacetate (9.6 mL, 87.2 mmol) in a freshly prepared solution of Na (3.9 g, 170 mmol) in ethanol (95 mL) is added at 30° C. The reaction mixture is stirred at 30° C. for 2 h before it is diluted with EA and washed with 1 N aq. NaOH and brine. The organic extracts are dried over Na2SO4 and the solvent is removed in vacuo. The resulting brown oil (9.66 g) is dissolved in ethanol (365 mL) and diluted with 1 N aq. LiOH (365 mL). The mixture is refluxed for 1 h before the organic solvent is removed in vacuo. Solid material is filtered off and the filtrate is extracted twice with diethyl ether. The organic layer is extracted back with 1 N aq. LiOH and brine. The aq. extracts are acidified with aq. HCl (37%). The precipitate that formes is collected, washed with water followed by hexane, and dried under high vacuum to give rac-(1aS,5aR)-2-ethyl-1,1-dimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (3.6 g) as beige crystals. From the hexane washings a second crop (2.37 g) is obtained after evaporation of the solvent; LC-MS: tR=0.99 min, [M+1]+=237.24, 1H NMR (CDCl3): δ 3.00 (dd, J=5.9, 19.3 Hz, 1H), 2.84-2.70 (m, 3H), 1.92-1.86 (m, 2H), 1.28 (t, J=7.0 Hz, 3H), 1.12 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[CH:11][C:12]([NH2:13])=[C:14]([Br:23])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Nc1cc(Cl)c(OCc2ccccc2)cc1Br
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 125.3 %

Procedure:
To a suspension of 4-benzyloxy-3-chloroaniline (674 mg) and potassium carbonate (1.14 g) in dichloromethane (32 mL) was added dropwise a solution of bromine (1.25 g) in dichloromethane (16 mL) at −15° C. in one hour, and the mixture was stirred at −15° C. for 75 minutes. Water was added to the reaction mixture and this resulting mixture was stirred vigorously for additional 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.13 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:38])[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])C1C=CC=CC=1>[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:38])[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:29]([CH3:31])[CH3:30])[CH:32]([CH3:33])[CH3:34])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
10% Palladium on carbon was added to 3-(benzyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (21.7 g, 40.4 mmol) in dry THF (480 mL) under argon. The reaction mixture was degassed and placed under a hydrogen balloon and stirred for 16 hours. The atmosphere was replaced with argon and mixture was filtered through diatomaceous earth then the filtrate evaporated and dried under high vacuum for 1 hour to give the title compound (18.2 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C@H:18]1[C@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C@:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[C@H:20]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:19]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:29][C:25]1[C:24]([F:30])=[C:23]([C@@H:22]2[C@:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[C@H:20]([CH2:41][C:42]([CH3:44])([CH3:45])[CH3:43])[NH:19][C@H:18]2[C:16]([NH:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:17])[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3[nH]c(C(=O)O)cc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid ethyl ester (33 mg, 0.051 mmol) was dissolved in ethanol (15 mL), then 2N KOH (5 mL) was added and stirred 2 hours @ 50° C., then the temperature was warmed to 65° C. for 2 h, after cooling to 25° C., the reaction was diluted with water and extracted with ethyl acetate (3×). The organic phase was separated then concentrated under reduce pressure to chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid (24 mg, 76%) as a white powder. HRMS (ES+) m/z Calcd for C32H28Cl2F2N4O3+H [(M+H)+]: 625.1580 found: 625.1580.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([NH:13][CH3:14])[CH:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1.[CH:16](=O)[C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]3[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH3:14])[C@H:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CNC1CN(c2ccc(Br)cn2)CC1O
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(C)[C@@H]2CN(c3ccc(Br)cn3)C[C@H]2O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Dissolve 1-(5-bromo-pyridin-2-yl)-4-methylamino-pyrrolidin-3-ol (0.347 g, 1.28 mmol) in dichloroethane (10 mL) and add veratraldehyde (212 mg, 1.28 mmol), sodium triacetoxyborohydride (405 mg, 1.91 mmol) and acetic acid (125 mL, 2.18 μmol). Stir the mixture at room temperature overnight. Dilute with saturated sodium bicarbonate and extract the mixture with dichloromethane (3×). Dry the combined organic portions over sodium sulfate, filter, and evaporate. Purify the resulting residue by silica gel chromatography, eluting with 0-9% methanol (2N NH3)/CH2Cl2 to give 390 mg (72%) of the title compound as a white solid. MS/ES m/z (81Br) 424.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:31]1.C(OCC)(=O)C>C1COCC1>[C:6]([C:5]1[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:10][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31]2)=[N:3][C:4]=1[O:26][CH2:27][CH2:28][CH3:29])(=[O:7])[NH2:8]
Reactant: CCCOc1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOc1nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide (500 mg, 1.194 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (956 mg, 4.77 mmol) in THF (3 mL) was sealed in a vial and heated at 100° C. for 24 hrs. The reaction mixture was dissolved into ethyl acetate, washed with water, and concentrated. The solid material was chromatographed on an ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH:NH4OH)/CH2Cl2 gradient (10-100%) to give 530 mg of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)-6-propoxypyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=583.46.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)([O-])O.[Na+].O.[C:13]([CH:18]([CH2:56][O:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]([CH2:67][CH3:68])([CH3:66])[CH3:65])=[CH:60][CH:59]=1)[CH2:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([S:52](Cl)(=[O:54])=[O:53])[CH:26]=[C:27]([C:29](=[O:51])[NH:30][CH2:31][CH:32]([C:46]([CH2:49][CH3:50])([CH3:48])[CH3:47])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[CH:37][CH:36]=2)[CH:28]=1)=[O:22])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(#N)C>[C:13]([CH:18]([CH2:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([C:64]([CH2:67][CH3:68])([CH3:65])[CH3:66])=[CH:62][CH:63]=1)[CH2:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([S:52]([O-:54])=[O:53])[CH:26]=[C:27]([C:29](=[O:51])[NH:30][CH2:31][CH:32]([C:46]([CH2:49][CH3:50])([CH3:47])[CH3:48])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[CH:37][CH:36]=2)[CH:28]=1)=[O:22])([CH2:16][CH3:17])([CH3:14])[CH3:15].[Na+:5]
Reactant: CCC(C)(C)c1ccc(OCC(CNC(=O)c2cc(C(=O)NCC(COc3ccc(C(C)(C)CC)cc3)C(C)(C)CC)cc(S(=O)(=O)Cl)c2)C(C)(C)CC)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(C)(C)c1ccc(OCC(CNC(=O)c2cc(C(=O)NCC(COc3ccc(C(C)(C)CC)cc3)C(C)(C)CC)cc(S(=O)[O-])c2)C(C)(C)CC)cc1
Temperature: 30 °C
Yield: 82.8 %

Procedure:
To 2 g (0.016 mol) of sodium sulfite and 2.4 g (0.029 mol) of sodium hydrogen carbonate were added 100 ml of water and 20 ml of acetonitrile and the mixture was stirred at 30° C. To the mixture was added dropwise a solution of 10.5 g (0.013 mol) of 3,5-di-(2,4-di-tert-amylphenoxypropylcarbamoyl)benzenesulfonyl chloride obtained in the aforesaid step dissolved in 100 ml of acetonitrile. After stirring the resultant mixture for one hour, the reaction mixture was poured onto ice water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed thrice with cold water and dried over Glauber's salt. After filtrating away the Glauber's salt, the residue was concentrated to dryness to provide 8.6 g (yield of 82.8%) of a solid product.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:14]2[CH2:15][CH2:16][CH2:17][C:13]=2[N:12]([C:18]2[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=4[N:28]=3)[CH3:26])=[O:23])=[CH:20][C:19]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][C:10]1[C:14]2[CH2:15][CH2:16][CH2:17][C:13]=2[N:12]([C:18]2[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=4[N:28]=3)[CH3:26])=[O:23])=[CH:20][C:19]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1
Reactant: C[C@H](NC(=O)c1ccc(-n2nc(CNC(=O)OC(C)(C)C)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(-n2nc(CN)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 55 %

Procedure:
Prepared analogously to Example 17 from 4-[3-(tert-butoxycarbonylamino)methyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-trifluoromethylbenzamide and trifluoroacetic acid. Yield: 55%; Rf value: 0.25 (silica gel; dichloromethane/methanol=9:1); C24H22ClF3N6O (502.93); mass spectrum: (M−H)−=503/505 (chlorine isotope).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].CS(C)=O.Br.[Br:15][C:16]1[CH:17]=[N:18][C:19]([OH:22])=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[N:20]([CH2:7][CH3:8])[CH:21]=1
Reactant: Oc1ncc(Br)cn1
Reactant: CCI
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCn1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
With cooling with ice, potassium carbonate (13.2 g, 95.7 mmol) and ethyl iodide (2.84 mL, 35.6 mmol) were added to a dimethyl sulfoxide (130 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (7.0 g, 27.3 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=1/1) to obtain the entitled compound (3.34 g, 60%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.[CH:31](=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:31]([N:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1)[CH3:32]
Reactant: CC=O
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(n2cc(-c3cnc4ccc(Cc5nnc6ccc(C)nn56)cc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (50 mg, 0.126 mmol) in dichloromethane (3 mL) was added acetaldehyde (15 uL, 0.505 mmol). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (67 mg, 0.136) was added. After 1 hour the solution was diluted with dichloromethane (1.5 mL) and washed with sodium bicarbonate (1.5 mL). The aqueous layer was extracted further with dichloromethane (1.5 mL). The combined dichloromethane layers were washed with brine (3 mL) and dried over Na2SO4. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (4.8 mg, 9% yield). Analytical data presented in Table 2.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]4[CH2:16][CH2:15]4)[CH:12]=3)[C:7]([C:17]#[N:18])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:17]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:6]=1[B:19]([OH:24])[OH:20])#[N:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cn(C2CCC2)c2cc(C3CC3)ccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)n(C2CCC2)c2cc(C3CC3)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
Into a solution of 1-cyclobutyl-6-cyclopropyl-1H-indole-3-carbonitrile (2.0 g, 8.47 mmol) and triisopropyl borate (3.52 mL, 15.25 mmol) in THF (35 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 7.3 mL, 11.01 mmol). The mixture was stirred at −78° C. for 30 min, quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give the title compound as a solid (2.5 g, 70% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[N:33]=[CH:34][S:35][CH:36]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:32]3[N:33]=[CH:34][S:35][CH:36]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3cscn3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 105 °C

Procedure:
To a solution of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (32.6 mg, 0.0776 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (18.0 mg, 0.0854 mmol) in 1,4-dioxane (1.1 mL, 14 mmol) in a microwave reactor tube were added PS-PPh3-Pd (0.10 mmol/g loading; 45 mg, 0.0045 mmol; Argonaut) and a solution of Cs2CO3 (52.1 mg, 0.160 mmol) in H2O (0.33 mL, 18 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 min. Further 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (21 mg, 0.099 mmol) was added, and the reaction mixture was heated in the microwave reactor to 105° C. for 30 min. A solution of the remaining 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (61 mg, 0.29 mmol) in 1,4-dioxane (0.30 mL, 3.8 mmol) was added to the reaction mixture, which was then heated to 105° C. for 45 min. The resin was filtered off and washed with DCM. The combined filtrate and washings were diluted with DCM to 50 mL, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was submitted to MDP for purification. The product fractions were combined and dried in vacuo overnight. The product was chromatographed on an SCX column (500 mg/3 mL), and the fraction eluting with NH3/MeOH was concentrated and dried in vacuo to give the title compound as an off-white film. 1H NMR (CDCl3, 400 MHz): δ=8.91 (d, J=2.4 Hz, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.29 (dd, J=4.8, 8.0 Hz, 1H), 7.06 (dd, J=8.0, 8.8 Hz, 1H), 6.62 (q, J=6.8 Hz, 1H), 5.29 (brs, 2H), 1.91 (d, J=6.8 Hz, 3H). MS (ES+): m/z=423.90/425.88/427.86 (98/100/28) [MH+], 234.00 (25) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.33 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].[N:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N)CCC.Cl>C1(C)C=CC=CC=1.O>[CH:11]([C@@H:10]1[CH2:9][CH2:8][C@@H:7]([CH3:14])[CH2:6][C@H:5]1[O:4][C:2](=[O:3])[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCN
Product: CCCCNC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
66.6 g of menthyl chloroformate (70% in toluene) were added to a mixture of 16.6 g of pyridine and 21.9 g n-butylamine in 100 mL toluene at 0° C. over a period of 50 minutes. After stirring for 12 hours at room temperature, 100 mL of 2M HCl and subsequently 50 mL water were added, the phases separated and the water phase discarded. After washing with saturated NaHCO3-solution and water the organic phase was dried and evaporated to yield 55.1 g of crude product which was recrystallized from 30 g n-heptane to give 34.5 g of the analytically pure product as white crystals.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])=O)=CC=1)([O-])=O.[C:23]1([C:29]([NH:42][C@@H:43]([CH2:46][NH2:47])[CH2:44][OH:45])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH:13]([O:12][P:11]([C:9]([NH:47][CH2:46][C@H:43]([NH:42][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:44][OH:45])=[O:8])([O:16][CH:17]([CH3:19])[CH3:18])=[O:20])([CH3:15])[CH3:14]
Reactant: NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)C(=O)NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisopropyl 4-nitrophenoxycarbonylphosphonate (i-Pr-NPPF) (9.27 g, 28 mmol) in dry CH2Cl2 (50 mL) was added dropwise to a solution of (S)-2-triphenylmethylamino-3-aminopropanol (9.3 g, 28 mmol) in dry CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Workup was done by washing the reaction mixture successively with 0.5 M NaOH and water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by column chromatography (silica gel, 70% EtOAc in pet. ether) to provide (S)-3-diisopropylphosphonoformamido-2-(tritylamino)propanol as gummy solid in 82% (12.0 g) yield.
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[O:7]1[C:6]2[CH:10]=[CH:11][C:3]([C:22]3([OH:25])[CH2:23][CH2:24][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 1.46 g of magnesium shavings, which had previously been covered with tetrahydrofuran, was added dropwise a solution of 12.06 g (60 mmol) of 5-bromo-benzo[1,3]dioxol in 30 ml of absolute tetrahydrofuran, followed by 11.35 g (60 mmol) of 1-benzyl-4-piperidone. The reaction mixture was stirred at 50° C. for 1 hour, then poured on to ice and ammonium chloride solution. The 4-benzo[1,3]dioxol-5-yl-1-benzyl-piperidin-4-ol formed was extracted with ethyl acetate and crystallized upon concentration of the solution. There were obtained 10.85 g (58% of theory) of white crystals; m.p.: 144° C.