Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([OH:28])[CH2:11]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)[C:13](=[O:27])[CH:12]([OH:28])[CH2:11]1
Reactant: COc1cccc(F)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1C(O)CC(c2c(O)cccc2F)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (−78° C.) solution of rac-(3R*,5S*)-5-(2-fluoro-6-methoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (compound corresponding to example 293; 355 mg; 0.88 mmol) in anh. DCM (8 ml) was treated dropwise with a solution of boron tribromide BBr3 (1.0 M in DCM; 4.45 ml; 4.45 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water was added dropwise to the cooled (0° C.) reaction mixture, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording rac-(3R*,5S*)-5-(2-fluoro-6-hydroxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 386.05 g/mol.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33][NH2:34])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33][NH:34][CH2:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115 mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol). After stirring at room temperature over night, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4, filtered and concentrated and residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give colorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s, 9H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[O:32].O>CCCCCC.O1CCCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:31]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[OH:32])[CH:33]=1
Reactant: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
33.8 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise under argon to a solution of 17.4 g 1-bromo-4-triisopropylsilylethynyl-benzene in 120 ml dry tetrahydrofuran chilled to −78° C. The solution is stirred for 1 h at −70° C. Then 10.8 g 5-bromo-2-fluoro-benzaldehyde dissolved in 30 ml of tetrahydrofuran are added dropwise over 15 min. The resulting solution is left in the cooling bath to warm up overnight to ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:44][O:43][C:41]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)=[O:42]
Reactant: COC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a trifluoroacetic acid salt (57.1 mg, Example 59) in dichloromethane (2 mL) were added triethylamine (58 mg, 8 equiv, Aldrich) and methyl chloroformate (6.7 mg, 1 equiv, Aldrich) at 0° C. After stirring for ˜2 hours at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (23.7 mg). MS (M+H)+, 404.
Reaction SMILES: CC(C)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:16][C@H:17]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:23]3[CH2:24][C:25]([CH3:39])=[C:26]2C(=O)C)[CH2:18]1.Cl.NO.C(NC1C=CC(S(Cl)(=O)=O)=CC=1)(=O)C.N1C=CC=CC=1.C(NC1[C@]2(CC[C@H]3[C@@H](CC=C4[C@]3(C)CC[C@H](C)C4)[C@@H]2CC=1C)C)(=O)C>C(O)C.O1CCCC1.Cl.N1C=CC=CC=1>[CH3:16][C@H:17]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:23]3[CH2:24][C@@H:25]([CH3:39])[C:26]2=[O:3])[CH2:18]1
Reactant: CC(C)=O
Reactant: CC(=O)C1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)NC1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]32)C1

Procedure:
To a solution of 16β-methyl-3β-hydroxy-5,16-pregnadien-20-one was added toluene, ethylene glycol, and p-toluene-sulfonic acid. The resulting solution was refluxed overnight forming the 20-ketal. The procedure for this ketalization step is described in JACS, 76, 5674 (1954). Tosyl chloride in pyridine was added to the above product to form the 3β-tosylate derivative. The 3β-tosylate was refluxed overnight with 10% NaI/acetone to form the 3β-iodo-16-methyl-5,16-pregnadien-20-one-ethylene ketal. This product was methylated with lithium dimethylcuprate in ether and tetrahydrofuran at -78° C. under a nitrogen atmosphere to form the 3β,16-dimethyl-5,16-pregnadien-20-one ethylene ketal. This product was deketalized by refluxing in the presence of acetone/p-toluenesulfonic acid. The resulting 3β,16-dimethyl,5,16-pregnadien-20-one was converted to the C-20-oxime by refluxing in ethanol and pyridine with an excess of hydroxylamine hydrochloride. This product was subjected to a Beckmann rearrangement in the presence of p-acetamidobenzenesulfonyl chloride/pyridine according to the procedure by Rosenkranz, et al. in J. Org. Chem., 21, 520-522 (1956). The product, 17-acetamido-3β,16-dimethyl-5,16-androstadiene was refluxed in tetrahydrofuran/hydrochloric acid solution. 3β,16α-dimethyl-5-androst-en-17-one was formed, separated and purified by normal phase HPLC using a 1 in.×25 cm silica gel preparative column at a flow rate of 30 ml/min and using ethyl acetate/hexane (in a gradient ranging from 0 to 20%) as the eluent. The product was recrystallized from methanol and characterized by NMR and IR. Colorless crystals were isolated:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1Cl.[F:14][C:15]([F:28])([F:27])C1C=CC=CC=1CCC(O)=O>>[ClH:2].[F:14][C:15]([F:28])([F:27])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Agent: Cl
Product: NCCCc1ccccc1C(F)(F)F

Procedure:
Intermediate 4 was prepared according to the procedures described in Intermediate 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid as the starting material. LC-MS (ESI) m/z 204.0 (M+H)+, RT=1.40 min (Method B).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([C:17]1[C:18]([NH:23][C:24](=O)[O:25]CC)=[N:19][CH:20]=[CH:21][CH:22]=1)=O.[BH4-].[Na+].C1(C)C=CC=CC=1>CO.C(O)(=O)C>[O:25]=[C:24]1[NH:23][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][N:1]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)Nc1ncccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccnc3NC2=O)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
4-Amino-1-N-Boc-piperidine (290 mg, 1.4 mmol) was added to a solution of ethyl 3-formylpyridin-2-ylcarbamate (240 mg, 1.2 mmol) in methanol (10 mL). Mixture was warmed to 60° C. and held for 1.5 hours. Mixture was cooled to room temperature. Sodium borohydride (62 mg, 1.6 mmol) was added to the mixture. Reaction stirred at room temperature for 30 minutes. Toluene (20 mL) was added to the mixture followed by acetic acid (1.0 mL). Mixture was warmed to 110° C. Methanol was driven from the reaction mixture and collected in a Dean-Stark trap. Mixture was held at 110° C. for 5 hours. Mixture was cooled to room temperature and held for 16 hours. Reaction was quenched with aqueous sodium bicarbonate. Mixture was extracted with ethyl acetate (2×30 mL). Combined organics were washed successively with water (30 mL) and brine (20 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white solid in 44% yield. MS m/e (M−H)−=311.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=431.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:2]2[N:7]=[C:6]3[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]3=[CH:4][CH:3]=2)[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCN(C)CC3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (520 mg, 1.47 mmol, Eq: 1.00), palladium (II) acetate (165 mg, 736 μmol, Eq: 0.5) and tri-tert-butylphosphine (149 mg, 182 μl, 736 μmol, Eq: 0.5) were combined with toluene to give a yellow solution. 1-methylpiperazine (442 mg, 491 μl, 4.41 mmol, Eq: 3) and sodium tert-butoxide (424 mg, 4.41 mmol, Eq: 3) were added. The reaction mixture was heated to 80° C. and stirred for 1 h. The reaction mixture was poured into 20 mL EtOAc and extracted with sat NaCl (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 2% to 5% MeOH in DCM) to give 6-(4-methylpiperazin-1-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (326 mg, 60%) as yellow oil that solidified upon standing.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1.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>CN(C=O)C>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[N:20]=[CH:21][C:22]([C:23]([NH:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])=[O:25])=[CH:26][CH:27]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Reactant: CCC(N)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminopentane (147 μl) in DMF (8 ml) was added to a mixture of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid (Intermediate 8, 200 mg), HATU (228 mg) and DIPEA (348 μl) in DMF (8 ml) and the reaction stirred for 18 hours at room temperature. The DMF was evaporated under vacuum and the residue dissolved in ethyl acetate and applied to an SCX SPE (10 g). The SPE was washed with ethyl acetate then methanol/ethylacetate (1:9) and the product elutes with 0.880 ammonia/methanol/ethyl acetate (1:1:8). The product fraction was reduced to dryness under vacuum and purified on a silica SPE (500 mg) eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvents 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[NH2:25][CH:26]([CH3:40])[C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:28].C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])[C:5]2[N:6]([C:8]([C:12]([NH:25][CH:26]([CH3:40])[C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:28])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CC(N)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NC(C)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
164 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 16A, 0.47 mmol, 1 equivalent) were dissolved in 1.4 ml of DMF, 145 mg of benzyl [(2S)-3-aminobutan-2-yl]carbamate (Example 141A, 0.65 mmol, 1.4 equivalents), 230 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.6 mmol, 1.3 equivalents) and 180.7 mg of N,N-diisopropylethylamine (0.23 ml, 1.4 mmol, 3 equivalents) were added and the mixture was stirred at RT overnight. A drop of water was then added and the precipitated solid was filtered off and dried under reduced pressure. This gave 160 mg (53% of theory; purity 86%) of the title compound as colourless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)C(=O)C(F)(F)F.[OH-].[Na+].[ClH:18].C(O)C>CO.O>[ClH:18].[ClH:18].[CH3:1][NH:2][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(Cc1cccnc1)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CNCc1cccnc1
Yield: 95 %

Procedure:
3.71 g of N-methyl-N-(3-pyridylmethyl)trifluoroacetic acid amide was dissolved in a mixture of 20 ml methanol and 20 ml water, and then stirred with 1.36 g of sodium hydroxide at room temperature for 6 hours. The reaction mixture was made acidic (pH 2) with concentrated hydrochloric acid on ice, and the resulting acidic solution was concentrated under reduced pressure to give a residue. After addition of ethanol, the residue was filtered to remove the precipitated inorganic salts. The filtrate was concentrated under reduced pressure, dried and then recrystallized from methanol/ethanol to give 3-(methylaminomethyl)pyridine dihydrochloride (3.16 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](I)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:4]2[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1cc(Cl)cnc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5.63 g (22.0 mmol) sample of 5-chloro-2-iodo-3-pyridinol, from step 7a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.377 g, 1.98 mmol) and triethylamine (1.90 mL, 13.6 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 2.04 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.3, 1.45 (2 s, 9H), 1.94-2.3 (m, 4H), 3.45-3.65 (m, 2H), 4.97-5.1 (m, 1H). 6.66 (s, 1H), 7.70 (s, 1H), 8.47 (s, 1H); MS m/z: 323 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[CH3:10])[CH:7]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH3:10])[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 40.2 %

Procedure:
5-Fluoro-N-(1-(3,5-dimethoxyphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C25H34N4O6: 486.25; Observed: 509.3 (M++Na).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.B(OC)(OC)[O:28]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[F:1][C:2]1[C:3]([OH:28])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9][C:10]=2[C:11]=1[F:12]
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3C2)CC1
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3cc(O)c(F)c(F)c3C2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
77.0 g (about 0.26 mol) of crude 7,8-difluoro-2-(4-propylcyclohexyl)-1,2,3,4-tetrahydronaphthalene are initially introduced in 500 ml of THF, and 200.0 ml (0.32 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 3 h at this temperature, 37.0 ml (0.33 mol) of trimethyl borate are added dropwise, the batch is warmed to 0° C., and 80 ml of dilute acetic acid (about 30%) are added. The mixture is warmed to 30° C., and 70 ml of hydrogen peroxide solution (35%) are carefully added. When the addition is complete, the mixture is stirred at RT for 2 h. Water is added, and the batch is acidified using dil. hydrochloric acid. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, toluene). The further purification is carried out by crystallisation from n-heptane, giving 3,4-difluoro-6-(4-propylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol as a colourless solid.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH3:15].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[CH3:15]
Reactant: CC(O)c1ccc(Cl)cc1Br
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Neat methanesulfonyl chloride (0.40 mL, 5.1 mmol) was added to a 0° C., DCM solution (20 mL) of 1-(2-bromo-4-chlorophenyl)ethanol (1.2 g, 5.1 mmol) and Et3N (0.78 mL, 5.6 mmol) and the resulting mixture was allowed to warm to room temperature gradually. After 30 min, Et3N (0.78 mL, 5.6 mmol) and 4′-chloro-[1,1′-biphenyl]-4-amine (1.0 g, 5.1 mmol) were added sequentially and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.