Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[N:28][C:5]2S[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1.O.OO.[OH:33][S:34]([O-:36])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:29]=[N:28][C:5]2[S:34](=[O:36])(=[O:33])[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCSc2ncc(Cl)cc21
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ncc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-chloro-1-(5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine (30 mg, 0.071 mmol) in EtOAc (2.5 mL) was added disodium tungstate (2.08 mg, 7.09 μmol) and water (0.2 mL). The reaction was cooled at 0° C. and then H2O2 (36.2 μL, 0.355 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (5 mg) was added followed by H2O2 (0.3 mL) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (10 mL). The separated organic layer was washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo to give 7-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. Mass Spectrum (ESI) m/e=455.0 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)[CH2:2][CH3:3].C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([NH2:16])[C:7]3[N:17]=[C:4]([CH2:1][CH2:2][CH3:3])[S:5][C:6]=3[C:15]=2[CH:14]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2s1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3ccc(Br)cc3c2s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 189.2 %

Procedure:
2-Propylthiazolo[4,5-c]quinolin-4-amine (1.0 g, 0.41 mmol) was combined with acetic acid (15 mL) and heated to 60° C. Bromine (0.10 mL, 1.94 mmol) was added dropwise and the reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water and the resulting precipitate was isolated by filtration to provide 0.25 g of 8-bromo-2-propylthiazolo[4,5-c]quinolin-4-amine as a yellow solid, m.p. 177-180° C. Analysis: Calculated for C13H12BrN3S: % C, 48.46; % H, 3.75; % N, 13.04; Found: % C, 47.98; % H, 3.95; % N, 12.70.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:20][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][N:17]=2)[CH:5]=[CH:4][N:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:2]2[CH:7]=[C:6]([CH2:8][S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[O:20][C:19]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[N:18][N:17]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Fc1cc(CSc2ccccc2-c2nnc(Nc3ccccc3)o2)ccn1
Product: c1ccc(Nc2nnc(-c3ccccc3SCc3ccnc(NC4CC4)c3)o2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To 5-(2-(2-fluoropyridin-4-yl) methylthiophenyl)-N-phenyl-1,3,4-oxadiazol-2-amine (80 mg, 0.19 mmol; Compound 1-(48)) was added cyclopropylamine (200 μL) at room temperature and then the mixture was stirred at 150° C. for 2 hours. The reaction solution was concentrated under a reduced pressure and the residue was purified with a silica gel column chromatography (hexane/ethyl acetate) and to give 5.0 mg (6%) of the titled compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])([OH:15])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29](S(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CS(C)=O.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>[ClH:1].[Cl:22][C:23]1[CH:24]=[C:25]2[C:31]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])([OH:15])[CH2:10]4)[C:5]([F:21])=[CH:4][N:3]=3)=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(=O)NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
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: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: CC(=O)NC[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: Cl
Temperature: 130 °C

Procedure:
N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]-methyl}-acetamide, 46c, (0.2 g, 0.6 mmol) was dissolved in acetonitrile (6 mL) and treated with 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.5 g, 1.2 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). Aqueous 2M sodium carbonate (3.0 mL, 6.1 mmol) was added, and the vial was sealed and heated in the microwave to 130° C. for 30 min. The organic layer was collected and concentrated in vacuo to provide the crude product, which was dissolved in DMSO and purified by HPLC using 5-70% MeOH/H2O with 6 mM HCl over 15 minutes to provide after concentration 75 mg of N-{[(1S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]methyl}acetamide hydrochloride as an off-white crystalline solid.
Reaction SMILES: C(OC([NH:8][C:9]([NH:11][C:12](=[O:34])[CH2:13][O:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[C:24]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[NH:10])=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[C:9]([NH:11][C:12](=[O:34])[CH2:13][O:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[C:24]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N=C(N)NC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 60 °C
Yield: 52 %

Procedure:
190 mg (0.408 mmol) of N—(N-(tert-butoxycarbonyl)carbamimidoyl)-2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetamide were dissolved in 2 ml of ethanol before adding 1.020 ml (4.08 mmol) of a 4N hydrochloric acid solution in dioxane. The solution was heated to 60° C. for 2 h. The solvent was evaporated in vacuo. By cooling, the crystallised solid was filtered and washed with ethanol. 85 mg (yield=52%) of N-carbamimidoyl-2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)acetamide hydrochloride were obtained as a yellow solid. LC-MS: m/z=366 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 11.36 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.55 (d, J=28.4 Hz, 4H), 7.92-7.71 (m, 4H), 7.44-7.31 (m, 3H), 4.99 (s, 2H), 4.40 (s, 2H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]=1[CH2:36]Br>C1COCC1.C(O)(=O)C>[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]=1[CH2:36][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
n-Butyllithium in hexanes (1.6 Molar (hereinafter “M”), 3.75 millilitre (hereinafter “ml”), 6.0 millimole (hereinafter “mmol”)) was added to di-isopropylamine (0.84 ml, 6.0 mmol) in dry THF (15 ml) at −10° under nitrogen. After 5 minutes (hereinafter “min”). the solution was cooled to −70° and tert-butyl acetate (0.5 ml, 3.71 mmol) added dropwise. After stirring at −70° C. for 10 min. under nitrogen, 4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (0.405 grams (hereinafter “g”), 0.92 mmol) in dry THF (15 ml) was added, and the mixture stirred at −70° for 2 h. Glacial acetic acid (2 ml) was added, the temperature allowed to rise to 22° and the solution evaporated in vacuo. The residue was purified by column chromatography over silica (50 g) eluting with cyclohexane-ethyl acetate (9:1)-(5:1) to give the product as an oil (0.21 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][CH:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Si:20]([O:21][CH:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:3][C:4]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[CH:5][N:6]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: N#Cc1cc(-c2cnc(Br)s2)ccc1F
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 85 °C
Yield: 32 %

Procedure:
Prepared using General Procedure 1. To 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy) silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1 mmol) in dioxane (1.8 mL) and H2O (0.2 mL) was added tetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). The solution was degassed with N2 and the reaction mixture heated at 85° C. for 6 h. Upon cooling, the reaction mixture was diluted with brine and washed with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (30% EA/Hexanes) to produce 0.05 g (32%) of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzo-nitrile as a white solid. LCMS-ESI (m/z) calculated for C25H27FN2OSSi: 450.6; found 451.1 [M+H] +, tR=4.84 min (Method 3).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc3sc(C)nc3c2Cl)c1
Yield: 84 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with m-anisoyl chloride (41 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-3-methoxy-benzamide (70 mg, 0.21 mmol, 84% yield) as a orange powder after crystallisation in hexane/DCM.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:29])=[C:22](C=[CH:27][CH:28]=1)C(O)=O.[C:30]([OH:33])(=[O:32])[CH3:31]>CS(C)=O>[C:30]([C:31]1[CH:27]=[CH:28][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])=[C:21]([CH3:29])[CH:22]=1)([OH:33])=[O:32]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: CC(=O)O
Solvent: CS(C)=O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccc(C(=O)O)cc3C)c2cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-amino-2-methylbenzoic acid (0.035 g, 0.23 mmol) and acetic acid (40 μl) in DMSO (0.8 ml) was stirred at 100° C. for 5 h. After cooling the reaction mixture was washed several times with diethyl ether. The oily residue was dissolved in water and made alkaline with 1 M NaOH and then weakly acidified with acetic acid. The mixture was left at 5° C. over night and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (35 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2F)[N:5]=[CH:4][C:3]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.Cl.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1
Reactant: C1CCNCC1
Reactant: Nc1c(C(=O)c2cccc(C=O)c2)cnn1-c1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2cccc(CN3CCCCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
To a solution of 5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl]pyrazole (0.3 g, 0.92 mmol), piperidine (0.1 ml, 1.0 mmol), acetic acid (0.05 ml) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.29 g, 1.37 mmol). After stirring at room temperature for 12 hours, the reaction was diluted with 10% hydrochloric acid and ethyl acetate (10 ml). The aqueous layer was separated and neutralized to pH 9 with sodium hydroxide and was then extracted with ethyl acetate. The combined organics were separated and washed with brine (25 ml), dried over MgSO4 and then concentrated in vacuo to a brown oil. The oil was purified by flash column chromatography using 1:1 hexanes/ethyl acetate to remove impurities and ethyl acetate to elute the desired product. Concentration of the column fractions in vacuo gave 5-amino-1-(4-fluorophenyl)-4-[3-(1-piperidinylmethyl)-benzoyl]pyrazole as an oil (0.211 g). The compound was triturated to a solid from hexanes/ethyl acetate.
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:10][NH:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:18])(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[C:16]2[CH:29]=[CH:30][CH:31]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)([CH3:33])[CH3:32])[CH:15]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Yield: 83.6 %

Procedure:
3-{2-[(2R)-2-(tert-butydimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-chlorophenyl)ethyl]benzamide (Preparation 38) (470 mg, 0.77 mmol) and ammonium fluoride (280 mg, 7.70 mmol) in methanol (3 ml) and water (1.7 ml) were heated to 43° C. for 18 hours. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume). The resulting compound was taken up in methanol and evaporated (×3) to yield a white foam (320 mg). A small sample was recrystallised (hexane:ethyl acetate) to give a white solid (mp 139-140° C.).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17].C(N1CCC(CNC(C2C3C(=CC=CC=3)NC=2)=O)CC1)CCC>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[Cl:1])=[O:13])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1CCC(CN)CC1
Reactant: O=C(O)c1c(Cl)[nH]c2ccccc12
Agent: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Product: CCCCN1CCC(CNC(=O)c2c(Cl)[nH]c3ccccc23)CC1

Procedure:
2-Chloroindole-3-carboxylic acid (L. Marchetti and A Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N-(1-n butyl-4-piperidyl)methylamine (D 1) using the procedure of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 2-chloroindole-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=2[F:32].C(Cl)Cl.Cl.[CH3:37][NH:38][CH3:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH3:37][N:38]([CH3:39])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=5[F:32])[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H]1C[C@H](n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CN1
Reaction time: 0.02 h

Procedure:
To a solution of (2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00889 mmol) in DCM (2 mL, 0.02 mol) was added dimethylamine hydrochloride (20 mg, 0.2 mmol) and DIPEA (0.2 mL, 1.0 mmol), and stirred for 1 min. TBTU (5.71 mg, 0.0178 mmol) was then added, and the solution was stirred at rt for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH/DCM. The band containing the product was collected and the product was eluted with 1:1 MeOH/DCM. The solution was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.22 (m, 1H), 2.82-2.90 (m, 1H), 2.99 (s, 3H), 3.10-3.13 (m, 3H), 3.21-3.26 (m, 1H), 3.49 (dd, J=12.3, 3.2 Hz, 1H), 4.15 (t, J=8.2 Hz, 1H), 4.99-5.05 (m, 1H), 7.38 (dd, J=9.6, 8.3 Hz, 1H), 7.84-7.91 (m, 2H), 8.13-8.17 (m, 2H), 8.27 (d, J=2.3 Hz, 1H), 8.43 (s, 1H), 9.60 (s, 1H). MS (ES+): m/z=480.13/482.11 (100/36) [MH+]. HPLC: tR=1.89 min (ZQ2, polar—5 min).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(N(CC1C=CC=CC=1)[C:17](=[O:22])[CH2:18][CH2:19][O:20][CH3:21])C>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:17](=[O:22])[CH2:18][CH2:19][O:20][CH3:21])[CH:12]=[CH:11][CH:10]=1
Reactant: CCN(Cc1ccccc1)C(=O)CCOC
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC(=O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of n-Butyllithium (1.6M in hexanes, 4.06 mL, 6.50 mmol) in anhydrous THF (4.0 mL) under nitrogen at −78° C. was added a solution of 2,6-dibromopyridine (1.54 g, 6.50 mmol) in anhydrous THF (9.5 mL) drop-wise over 45 min. The resulting dark green solution was stirred at −78° C. for 15 min and then treated with N-ethyl-3-(methyloxy)-N-(phenylmethyl)propanamide (2.16 g, 9.76 mmol), washing in with anhydrous THF (3.0 mL). The resulting green solution was stirred at −78° C. for 15 min and was then treated with a solution of AcOH (0.40 mL) in MeOH (6.60 mL) to give a pale brown solution. This mixture was removed from the cooling bath and allowed to warm to room temperature, then stirred for 2 h. The mixture was then treated with saturated aqueous. NH4Cl (40 mL) and the products extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (60 mL), dried (MgSO4) and the reduced in vacuo to give an orange oil. Purification by Biotage (silica, 90 g cartridge) eluting with cyclohexane:EtOAc (10:1) afforded the title compound as a white solid (547 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[CH:17]=[C:16]([C:18](=O)[CH3:19])[C:15]([CH3:21])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:22].NO.[OH-].[Na+].C[N:28]([CH3:31])C=O>>[CH2:6]([N:13]1[CH:17]=[C:16](/[C:18](/[Cl:22])=[CH:19]/[C:31]#[N:28])[C:15]([CH3:21])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)c1cn(Cc2ccccc2)nc1C
Reactant: Cl
Reactant: CN(C)C=O
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccccc2)cc1/C(Cl)=C/C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To N,N-dimethylformamide (13.4 g) was added phosphorus oxychloride (28.1 g) by small portions under ice-cooling, and the mixture was stirred at room temperature for 15 min. Thereto was added 1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)ethanone (9.80 g) produced above by small portions under ice-cooling, and the reaction mixture was stirred at 50° C. for 30 min. Thereto was added hydroxylamine hydrochloride in a powder (25.4 g) at 50° C. by small portions, and the reaction mixture was stirred at 50° C. for 30 min. Ice water (200 mL) was added to the reaction mixture, and the mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from diethyl ether to give the title compound (5.73 g) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:18]1([N:12]([C@@H:8]2[CH2:7][C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)[CH:13]([CH3:15])[CH3:14])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC1
Reactant: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
(R)-8-Fluoro-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.96 g, 8.19 mmol) was dissolved in anhydrous methanol (20 mL) and to this was cyclobutanone (6.1 mL, 81.9 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (2.0 g, 16.4 mmol) was added, the pH was adjusted to 4-5 with acetic acid, 3 Å molecular sieves were added and the reaction was allowed to stir at room temperature overnight. After 24 h the pH-was again adjusted to 4-5 and the reaction was allowed to stir for 3 more days. The reaction was filtered, solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4) filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 10% ethyl acetate/hexane) gave 1.60 g (77% yield) of the title compound as a clear oil. [α]21D =-95.1° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (3%).