Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 35.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (69 mg, 0.78 mmol), N-methylmorpholine (81 mg, 0.78 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 74 mg, 35.9%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:27]=1[NH2:28].CN(C=O)C>CC(O)CCC>[OH2:13].[ClH:2].[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:27]=1[NH:28][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: O
Yield: 228.2 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (205 mg, 0.5 mmol), (prepared as described for the starting material in Example 7), and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (10 ml) and DMF (1 ml) was heated at reflux for 5 hours. The resulting solid was collected by filtration, partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. The organic layer was separated and purified by column chromatography eluting with methylene chloride/methanol (70/30). The purified solid product was dissolved in ethanol and concentrated hydrochloric acid (0.2 ml) added. The volatiles were removed by evaporation and the residue was recrystallised from isopropanol/ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride hydrate (283 mg, 73%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[Mg:12]>O>[CH:1]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg+2:12].[CH:1]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Mg]
Reactant: O=C(O)C1CCCCC1
Solvent: CO
Solvent: O
Product: O=C([O-])C1CCCCC1
Product: [Mg+2]

Procedure:
128g of cyclohexylcarboxylic acid was added to a three dm3 flask containing 400 cm3 of methanol and 600 cm3 of water. This mixture was stirred whilst 12.2 g of magnesium metal were added over a period of one hour. The mixture was left stirring overnight, during which time most of the magnesium had been consumed and a white precipitate of magnesium cyclohexylcarboxylate was produced. The flask was then warmed to 60° C. with stirring and the precipitate dissolved to give a clear solution. The clear solution was filtered (leaving behind about 0.5 g of magnesium) the filtrate was set aside to crystallise. Two crops of crystals were recovered having a total weight, after drying, of 125 g. The magnesium cyclohexylcarboxylate was dried in an oven for 2 hours at 120° C., and then stored under nitrogen. This will be identified as MgCR.
Reaction SMILES: [Cs].[CH3:2][CH:3]([CH3:15])[CH2:4][CH2:5][CH:6]1[N:10]([CH3:11])[S:9](=[O:13])(=[O:12])[NH:8][C:7]1=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1([S:28][CH2:29]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.CN(C=O)C>[C:22]1([S:28][CH2:29][N:8]2[C:7](=[O:14])[CH:6]([CH2:5][CH2:4][CH:3]([CH3:15])[CH3:2])[N:10]([CH3:11])[S:9]2(=[O:13])=[O:12])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 85 °C
Yield: 70.6 %

Procedure:
A mixture of 4-(3-methylbutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 retool) of the 1,1-dioxide in methanol with 5 5.13 g of Cs2CO3 followed by removal of the solvent) and phenylthiomethyl chloride (6.65 g, 41.94 mmol) suspended in DMF was heated at 85° C. for 17 hours. The mixture was cooled, and poured into 300 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3×) and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 g (70.6%) of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)CCOCCCl
Product: COc1ccc(CNC(=O)CCOCCCl)cc1

Procedure:
Title compound was prepared starting from 4-methoxyphenylmethanamine and 3-(2-chloroethoxy)propanoyl chloride following the procedure outlined for Example 27A. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 3.80 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 6.80-6.87 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:25]=[C:24]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]4)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford (2S)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1-methylpyrrolidine-2-carboxamide. (25 mg, 25%)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O>C(OC(C)=O)(C)(C)C>[C:1]1([CH2:7][C:8]([O:10][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 2-phenylacetic acid (12 g, 88 mmol) in tBuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid, 70% redistilled (0.212 mL, 3.53 mmol) stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Extensive bubbling was observed. The resulting layers were separated and the organic layer washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-phenylacetate, Intermediate S5A (11.6 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: C1(C2C(N3CCN(C(C4C=NC(F)=CC=4C)=O)CC3)=NC=C(C3CC3)C=2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].[NH2:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:62]3[C:67]([CH:68]4[CH2:70][CH2:69]4)=[CH:66][C:65]([CH:71]4[CH2:73][CH2:72]4)=[CH:64][N:63]=3)[CH2:58][CH2:57]2)=[O:55])=[C:50]([CH3:74])[CH:49]=1>>[CH:68]1([C:67]2[C:62]([N:59]3[CH2:58][CH2:57][N:56]([C:54]([C:51]4[CH:52]=[N:53][C:48]([N:47]5[CH2:40][CH2:41][CH2:42][S:43]5(=[O:45])=[O:44])=[CH:49][C:50]=4[CH3:74])=[O:55])[CH2:61][CH2:60]3)=[N:63][CH:64]=[C:65]([CH:71]3[CH2:73][CH2:72]3)[CH:66]=2)[CH2:69][CH2:70]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (410 mg) described in Preparation Example 178, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.24 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (295 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23].ClC1N=C(NCCNC(=O)OC(C)(C)C)[C:35](C#CC(OCC)OCC)=[CH:34]N=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]2([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:21][CH2:35][CH2:34][CH2:20]2)[C:2]([C:27]#[C:26][CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])=[CH:7][N:6]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: C#CC(OCC)OCC
Reactant: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NC1(CNC(=O)OC(C)(C)C)CCCC1)OCC

Procedure:
tert-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamate is synthesized by treating tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate. LCMS (ESI) 453 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:19]([O:26][C:27]1[C:36]2[O:35][CH2:34][C@H:33]([CH2:37]OS(C)(=O)=O)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[C:36]2[O:35][CH2:34][C@H:33]([CH2:37][N:1]3[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]4[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=4)[CH2:2]3)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Reactant: CS(=O)(=O)OC[C@H]1COc2c(OCc3ccccc3)cccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4c(OCc5ccccc5)cccc4O3)C2)c1
Yield: 33.4 %

Procedure:
A mixture of hydrochloride salt of (R*)-3-(piperidin-3-yl)-phenol (240 mg, 1.12 mmol) and sodium bicarbonate in N,N-dimethylformamide (3 ml) were stirred at +120° C. under nitrogen atmosphere. To this mixture, a mixture of methanesulfonic acid (R)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (390 mg, 1.11 mmol) in N,N-dimethylformamide (3 ml) was added, and stirred at +130° C. for 3.5 h. The reaction mixture was cooled down, water (20 ml) and ethyl acetate (15 ml) were added and the layers were separated. Organic phase was recovered and water layer was extracted twice with ethyl acetate. Organic phase and ethyl acetate extracts were combined and washed five times with water and saturated sodium chloride solution. The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified with flash chromatography using heptane and ethyl acetate as eluents to give 160 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CCC(=O)CCc2ccc(N)cc2)cc1

Procedure:
A mixture of 1,5-bis-(4-nitro-phenyl)-pentan-3-one from Example HH (9.00 g, 27.4 mmol), 5% Pd on BaSO4 (0.7 g), and THF (600 mL) was shaken in a hydrogen atmosphere of 52 psi at 26° C. for 17 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 4% MeOH in CH2Cl2, to give the title compound. 1H NMR (CDCl3) δ 2.60 (m, 4 H), 2.74 (m, 4 H), 3.45 (bs, 4 H), 6.56 (m, 4 H), 6.91 (m, 4 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH:51]([CH3:53])[CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][CH:14]([CH:51]([CH3:52])[CH3:53])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.71 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.29 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][CH3:23])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:24](N(CC)CC)C.C[N:32]([CH:34]=[O:35])C>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][N:22]([CH3:24])[CH2:23][C:34]([NH2:32])=[O:35])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CCN(CC)CC
Product: CN(CC(N)=O)C[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of [(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methyl-amine (0.08 g, 0.2.8 mmol) in dry DMF (2 mL) was added triethylamine (0.1 mL, 0.72 mmol) and 3-bromoacetamide (0.32 g, 0.24 mmol). The reaction mixture was stirred for six hours at 60° C., then cooled and quenched by addition of water. The reaction mixture was extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried (MgSO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (MeOH/methylene chloride 1/4) gave 0.08 g of 2-{[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methyl-amino}-acetamide as a foam. MS (M+H)=393.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:18][CH:17]([F:19])[C@@H:14]1[C@@H:13]2[C@@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([C:34]4[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[F:28])([N:9]=[C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:11][CH2:12]2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)F)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)F)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (2.70 g) and 5-methoxypyrazine-2-carboxylic acid (1.25 g, described in WO2009/091016), in DCM (30 mL) was added N,N-diisopropylethylamine (3.5 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (4.2 g). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 25% EtOAc in DCM gradient) to afford the title compound (1.74 g) as a white solid. NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.76-2.88 (m, 1H), 2.95-3.28 (m, 1H), 3.34-3.53 (m, 1H), 3.83-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.68 (m, 2H), 5.98 (dt, J=3.6, 56.8 Hz, 1H), 7.07-7.20 (m, 1H), 7.36-7.48 (m, 1H), 7.96-8.04 (d, J=7.8 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH3:19])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCI
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:28](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Iodomethane (1.22 mL, 19.63 mmol) was added in one portion to 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylic acid (6.72 g, 19.63 mmol) and potassium carbonate (3.26 g, 23.55 mmol) in DMF (60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 hours then quenched in water (200 mL) and extracted with MTBE (2×100 mL). The extract was washed sequentially with water (3×100 mL) and saturated brine, dried over MgSO4 and concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 35% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylate (5.09 g, 73%) as a colourless solid.