Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:11]([OH:16])[OH:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A solution of the Grignard reagent, prepared from 4-bromoanisole (80.0 g, 0.43 mol) and magnesium (11.96 g, 0.49 mol) in dry THF (300 ml) was added dropwise to a stirred, cooled (-78° C.) solution of tri-isopropyl borate (161.7 g, 0.86 mol) in dry THF (50 ml) under dry nitrogen. The stirred mixture was allowed to warm to room temperature overnight and was then stirred at room temperature for 1 h with 10% hydrochloric acid (300 ml). The product was extracted into ether (twice), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a cream-coloured solid (58.5 g) which was recrystallised from water to give colourless crystals.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1]([NH:8][C@H:9]([C:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1CCNC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1

Procedure:
10.0 g (53 mmol) BOC-alanine was coupled to 8.7 ml (105 mmol) pyrrolidine according to procedure B. Yield of active ester 14.97 g (52 mmol, 98%). Yield of crude product 10.97 g. The product was purified by a silica column using 50–100% ethyl acetate in petroleum ether as eluent. Yield 9.07 g (37.4 mmol, 72%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[CH3:25][N:26]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([NH:34][C:35]2[CH:43]=[C:42]([Sn](C)(C)C)[CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][N:39]3S(C2C=CC=CC=2)(=O)=O)=[O:33])=[N:27]1>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.CN(C=O)C>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[CH:5][NH:6]2)=[C:2]([C:42]2[CH:41]=[C:40]3[C:36]([CH:37]=[N:38][NH:39]3)=[C:35]([NH:34][C:32]([C:28]3[C:29]([CH3:31])=[CH:30][N:26]([CH3:25])[N:27]=3)=[O:33])[CH:43]=2)[CH:10]=1)#[N:12]
Reactant: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: N#Cc1cc(Br)c2ccn(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn(C)nc1C(=O)Nc1cc(-c2cc(C#N)cc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
4-Bromo-1-[(4-nitrophenyl)sulfonyl]-1H-indole-6-carbonitrile (70 mg), 1,4-dimethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-3-carboxamide (51 mg) and Pd(PPh3)4 (22 mg) were weighed to a microwave vial and DMF (1 ml) was added. The reaction was heated at 120° C. for 1 h, then cooled and passed through a silica (1 g) cartridge, which had been pre-washed with methanol and washed through with methanol:DCM. The solvent was dried under nitrogen blowdown. The residue was purified using MDAP (method K but using an isocratic 50:50 solvent mix over 10 min). Purified fraction was dissolved in methanol (1 ml) and 2M NaOH (aq) (2 ml) was added and the reaction left at RT over the weekend. The reaction was neutralised using 2M HCl (aq) and dried under nitrogen blowdown. The residue was taken into water and extracted into ethyl acetate. The ethyl acetate was passed through a hydrophobic frit, then through an SAX cartridge pre-conditioned with ethyl acetate. The solvent was evaporated by nitrogen blow down to give title compound, 12 mg.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(Br)cc(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1cc(Br)cc(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 118 mg (4.9 mmol) LiOH in 5 mL water was added to a solution of 2.0 g (3.3 mmol) of (R)-2-(3,5-dibromo-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 12.5 mL THF and the mixture was stirred for 2 h at RT. The reaction mixture was evaporated down i. vac., the residue was combined with water and TBME, the aqueous phase was adjusted to pH 2-3 with conc. HCl and extracted with DCM. The combined organic phases were washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness i. vac.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13](O)[N:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([Cl:21])[N:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc2c(nn1)CN(Cc1ccccc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc2c(nn1)CN(Cc1ccccc1)CC2
Temperature: 85 °C

Procedure:
To a slurry of 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-c]pyridazin-3-ol (7 g, 29.1 mmol) in toluene (50 ml) is added POCl3 (7 ml). The resulting mixture is heated at 85° C. for 3 hr. The mixture is cooled to 0° C. and is neutralized with saturated NaHCO3 solution. The mixture is extracted with EtOAc (100 ml×2). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by silica gel chromatography (EtOAc/4% TEA) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23].[Cl-].[NH4+].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:22]([N:21]([CH3:25])[CH3:20])=[O:23])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 6.48 g (30 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 150 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -60° C., 25 mL (61.5 mmol) 2.46M n-butyllithium in hexanes. The reaction mixture was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added dropwise a solution of 3.1 mL (33 mmol) of N,N-dimethylcarbamyl chloride in 10 mL of THF at such a rate as to maintain the temperature below -65° C. The reaction mixture was allowed to warm to room temperature and stir for ca. 1.5 hours. The reaction mixture was cooled to ca. 5° C. and 60 mL of 50% ammonium chloride solution was added. The reaction mixture was stirred for ca. 15 minutes. The pH was adjusted to ca. 3 with 1N HCl (ca. 30 mL), and the aqueous phase was separated from the THF phase and extracted with ethyl acetate. The combined THF and ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to an oil. The oil was chromatographed on silica with (20% ethyl acetate/80% n-butyl chloride) affording 4.33 g of the title compound as a pale yellow solid. 1H NMR(CDCl3, 200 MHz.) δ: 6.61(d,1H), 6.46(d,1H), 4.62(bs,1H), 3.59(s,3H), 3.1(s,3H), 2.95(s,3H), 1.24(s,9H).
Reaction SMILES: [CH3:1][C:2]12[CH:11]=[CH:10][CH:5]([CH:6]=[C:7]1[CH2:8][OH:9])[C:4]([CH3:13])([CH3:12])[C:3]2=[O:14].[H][H]>[C].[Pd].C(O)(C)C>[CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][CH:7]1[CH2:8][OH:9])[C:4]([CH3:13])([CH3:12])[C:3]2=[O:14]
Reactant: CC12C=CC(C=C1CO)C(C)(C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2(C)CCC1CC2CO
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A mixture of 30 g of 1,3,3-trimethyl-6-hydroxymethyl-bicyclo-(2.2.2)-octa-5,7-dien-2-one, 0.5 g of 5% of palladium-carbon and 300 ml of isopropyl alcohol is added to a stirred autoclave. The autoclave is pressurized to 400 pounds per square inch with hydrogen and heated to 100° C for 6 hours. At the end of this time, the mixture is filtered, stripped of solvent and vacuum distilled, yielding about 27 g (90%) of the product, 1,3,3-trimethyl-6-hydroxymethyl-bicyclo-(2.2.2)-octan-2-one, having the structure: ##SPC41##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[CH2:10](Br)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCc1ccccc1
Yield: 92.6 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.95 g of the desired compound (yield: 92.8%). The resulting compound was identified as 1-phenyl-3-(3-ethyl-4-pyridyl)-propane (hereinafter referred to as compound by the following analytical results.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@H:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[C@@H:18]([NH:21][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:19][CH3:20])[CH3:17]
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added (S)-butan-2-amine (93 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). The resulting solution was stirred for 3 hours at 70° C. and then quenched by the addition of water (10 mL). The solids were collected by filtration to afford (S)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as light yellow solid (150 mg, 65%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:21])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(OC)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (60 g, 0.20 mmol) in THF (3 mL) and H2O (2 mL) was added LiOH (0.048 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.050 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 6.94 (s, 1H), 5.56 (m, 1H), 4.40 (m, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.00 (m, 1H), 2.02 (m, 1H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 86% (220 nm), 96% (Maxplot).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.CC[N:35]([CH:39]([CH3:41])[CH3:40])C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:39]1([NH:35][C:6]([CH:4]2[CH2:3][C:2]([OH:1])([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH2:19][C:18]([C:24]5[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=5)([C:20]([F:23])([F:21])[F:22])[O:17][N:16]=4)=[CH:11][CH:10]=3)[CH2:5]2)=[O:7])[CH2:41][CH2:40]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.1 g, 0.196 mmol) in DMF (3 mL) was added DIPEA (0.051 g, 0.393 mmol), HOBt (0.027 g, 0.196 mmol), EDCl.HCl (0.057 g, 0.294 mmol) and cyclopropyl amine (0.011 g, 0.196 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (5×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), dried over sodium sulphate and evaporated in vacuo to get 0.2 g (crude). Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 0.7% methanol in DCM to afford off white solid (0.055 g, 51%. 1H-NMR (400 MHz, CDCl3) δ: 0.54-0.59 (m, 2H), 0.81-0.86 (m, 2H), 2.48-2.51 (m, 2H), 2.75-2.86 (m, 4H), 3.67 (d, 1H, J=17.16 Hz), 4.07 (d, 1H, J=17.16 Hz), 5.73 (s, 1H), 5.79 (bs, 1H), 7.54 (d, 2H, J=8.2 Hz), 7.62-7.63 (m, 4H); LC-MS (m/z): [M−H] 544.70,
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@@H:20]([C:32](=[O:33])[N:39]([CH2:38][C:37]4[CH:43]=[CH:44][CH:45]=[CH:46][C:36]=4[Cl:35])[CH:40]4[CH2:42][CH2:41]4)[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: Clc1ccccc1CNC1CC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N(Cc2ccccc2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233.3 mg, 0.5 mmol), (2-chlorobenzyl)-cyclopropylamine (99.9 mg, 0.55 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (2.5 mL), propylphosphonic anhydride solution (˜50% in DMF, 480 μL, ˜0.75 mmol) is added. The reaction mixture is stirred for 14 h at RT, diluted with ethyl acetate and washed twice with an aqueous NaHCO3 solution. The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the residue is purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with Na2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a white amorphous solid. MS: 630.7 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.24 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:31])[C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:5][O:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:32].O1CCOCC1>C(Cl)Cl>[ClH:32].[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:31])[C:26]=1[S:27]([CH3:30])(=[O:28])=[O:29])[CH2:5][O:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2cc(F)c(S(C)(=O)=O)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1c(F)cc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-butyl 4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step B product, 1.85 g, 4.03 mmol) was dissolved in DCM (20 ml) and HCl in dioxane (4 M solution, 10.60 ml, 40 mmol) was added. The mixture was stirred at RT for 1 h. The solvents were evaporated to afford 1.6 g (100%) of the desired product which was used without further purification. LC/MS (m/z): 360 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N:50]=[C:51]=[O:52])([O:42][CH3:43])=[O:41]>>[C:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:52])([O:42][CH3:43])=[O:41]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: COC(=O)c1ccccc1NC(=O)OC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4CC4)CC3C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N2C1
Yield: 40.5 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-carbomethoxyphenyl isocyanate (62 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 53 mg (41%) of 18-(2-carbomethoxyphenylaminocarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.6% pure (HPLC), MS m/z 746 (M−H)−, HRMS: calcd. 786.2423 and found 786.2436 (M−H+K)−, mp 147-149° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:19]=[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1

Procedure:
4-[1-(3-Bromo-phenyl)-piperidin-4-yl]-morpholine was prepared from 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol) and 3-bromophenylboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a tan resin (0.238 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=7.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.75-3.68 (m, 6H), 2.79-2.70 (m, 2H), 2.60-2.55 (m, 4H), 2.37-2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.68-1.56 (m, 2H). MS=325, 327 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 20 °C
Reaction time: 16 h

Procedure:
93 ml of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added dropwise to a solution of 10 g (46.5 mmol) of 4-bromo-3-methyl-benzoic acid in 100 ml of tetrahydrofuran at 0° C. under argon. After the reaction mixture has been heated to 20° C., it is stirred at this temperature for 16 hours. The excess borane complex is then destroyed by careful addition of water (end of the evolution of hydrogen), the mixture is extracted twice with in each case 250 ml of ethyl acetate and the combined organic phases are washed twice with in each case 100 ml of saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The compound is reacted further without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([C:17]4[C:18](F)=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]=[C:32]2[NH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].N.CO>C1COCC1.CC(O)=O.CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([C:17]4[C:18]([NH:26][C:27]5[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]6[C:36]=5[N:35]=[CH:34][N:33]=[C:32]6[NH:37][C:38]5[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=5)=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reactant: COc1ccc(Cn2ncc3c(-c4cccnc4F)ncnc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2ncc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)ncnc45)ncnc32)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (150 mg, 447 mmol) and 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (135 mg, 492 mmol) in THF (3 ml) was sonicated until the solid became a fine powder. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0 M solution in THF) (1476 μl, 1476 mmol) slowly. The mixture was stirred at it for 4 hr (LCMS: some SM) and then heated in a microwave synthesizer at 60° C. for 20 min The mixture was poured into MeOH (15 ml) and AcOH (0.5 ml) was added and then NH3/MeOH (2 M, 20 mL) was added. Solvent was removed in vacuo. The product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(8-(3-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS Found (ESI pos. ion) m/z 591 (M+H+).