Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](Cl)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]5[CH3:32])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:33]1(NC(C2C3C=C(C4C(C)=CN=C(Cl)N=4)SC=3C=CC=2)=O)CC1.C(OC(N1CCN(CCN)[C@H](C)C1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:33])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]5[CH3:32])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCN
Product: Cc1cnc(NCCN2CCNC[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of (R)-2-{5-chloro-2-[2-(2-methylpiperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (R)-4-(2-aminoethyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 451 [M+H].
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1)(=O)C.O.[SH2:21].[Na]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([SH:21])[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1
Reactant: COC(=O)c1nc2nc(COC(C)=O)cc(Cl)n2n1
Reactant: S
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc2nc(CO)cc(S)n2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
Methyl 5-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-2-carboxylate (380 mg) (1.33 mmol) are dissolved in 20 ml of methanol. After the addition of 296 mg (4 mmol) of sodium hydrogen sulphide monohydrate the mixture is stirred at 60° C. for 5 hours. The reaction mixture is concentrated and brought to pH 3 with dilute aqueous hydrochloric acid. The product is filtered off under suction, washed with water/methanol and crystallized from methanol. There are obtained 290 mg of methyl 5-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-2-carboxylate as a brown powder.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1.[CH3:24][O:25][C:26](=[O:40])[CH2:27][C:28]1[C:32]2[C:33]([CH3:39])=[CH:34][C:35](O)=[C:36]([CH3:37])[C:31]=2[O:30][CH:29]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:24][O:25][C:26](=[O:40])[CH2:27][C:28]1[C:32]2[C:33]([CH3:39])=[CH:34][C:35]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)=[C:36]([CH3:37])[C:31]=2[O:30][CH:29]=1
Reactant: COC(=O)Cc1coc2c(C)c(O)cc(C)c12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1coc2c(C)c(OCc3ccc(C)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a mixture of tri-n-butylphosphine (0.240 mL), (2,6-dimethylpyridin-3-yl)methanol (92 mg), methyl(6-hydroxy-4,7-dimethyl-1-benzofuran-3-yl)acetate (150 mg) and THF (6.0 mL) was added ADDP (242 mg) at room temperature. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated. To the residue was added. IPE and the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (163.9 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:53][C:54]1[CH:62]=[C:61]([CH3:63])[C:57]([C:58](O)=[O:59])=[C:56]([CH3:64])[N:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:53][C:54]1[CH:62]=[C:61]([CH3:63])[C:57]([C:58]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:59])=[C:56]([CH3:64])[N:55]=1
Reactant: Cc1ccncc1CN(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CCN)CC1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccncc1CN(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(Cl)nc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amine (72.9 mg, 0.17 mmol), EDCI (36.4 mg, 0.19 mmol) and HOBT (25.7 mg, 0.19 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 6-chloro-2,4-dimethyl-nicotinic acid hydrochloride salt (42.2 mg, 0.19 mmol) followed by DIPEA (66.3 μL, 0.38 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded 6-chloro-2,4-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-nicotinamide as a white foam (61.1 mg, 60%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=5 Hz), 1.23 (m, 1H), 1.40 (m, 1H), 1.65 (m, 3H), 1.76 (m, 1H), 1.91 (d, 2H, J=11 Hz), 2.24 (m, 1H), 2.30 (s, 3H), 2.41 (s, 3H), 2.51 (s, 3H), 2.61 (m, 1H), 2.85 (m, 3H), 3.40 (m 1H), 3.48 (s, 1H), 3.74 (m, 2H), 4.25 (s, 2H), 6.84 (dd, 1H, J=3 Hz, 9 Hz), 6.99 (s, 1H), 7.13 (d, 1H, J=5 Hz), 7.41 (m, 2H), 8.05 (d, 1H, J=3 Hz), 8.17 (s, 1H), 8.38 (d, 1H, J=5 Hz). ES-MS m/z 589 (M+H), 612 (M+Na). Anal. Calcd. For C30H36ClF3N6O: C, 61.17; H, 6.16; Cl, 6.02; F, 9.67; N, 14.27.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C@@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1.C(O)(C(F)(F)F)=O>>[C:18]1([CH3:17])[CH:19]=[CH:20][C:21]([S:24]([O-:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[C:10]([C@H:9]([NH2+:8][CH3:6])[C@@H:13]([OH:15])[CH3:14])([OH:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H](O)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[NH2+][C@@H](C(=O)O)[C@H](C)O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a heart-shaped flask, (2R,3S)-2-[tert-butoxycarbonyl-(methyl)-amino]-3-hydroxy-butanoic acid (0.086 g, 0.37 mmol) was mixed with p-TsOH (0.073, 0.39 mmol) and the solid mixture was cooled to 0° C. Subsequently TFA (2.0 mL) was added over 10 min and the reaction mixture was left to react for 15 min at 0° C. The solution was rotary evaporated maintaining the bath below 30° C. and the obtained oil was left under vacuum for 1 h. The oil was then dissolved in dry Et2O to form a white precipitate. The solution was decanted and the solid washed several times with the same solvent to give a pure product (0.11 g, quant.), as a white sticky solid. 1H NMR (DMSO-d6) δ 1.25 (d, J=6.5 Hz, 3H), 2.29 (s, 3H), 2.60 (s, 3H), 3.73-3.82 (m, 1H), 4.02-4.11 (m, 1H), 7.11 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14][CH3:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.C(N(CC)CC)C.C([Cl:28])(=O)OCC.[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][NH2:37])[CH3:30]>CC(C)=O>[ClH:28].[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][NH:37][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14][CH3:15])[CH:9]=1)=[O:13])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: CSc1cc2c(c(C(=O)O)c1)OC(C)C2
Reactant: CCN1CCCC1CN
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(SC)cc2c1OC(C)C2
Product: Cl
Temperature: 10 °C
Reaction time: 15 h

Procedure:
2-Methyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxylic acid, 4.6 g, is dissolved in 50 ml of acetone, 6.9 ml of triethylamine is added and the whole is stirred. Under cooling at 10° C. 2.7 g of ethyl chlorocarbonate is added dropwise for 3-5 minutes. After stirring at room temperature for 30 minutes, 3.4 g of 1-ethyl-2-aminomethylpyrrolidine is added and the reactant is stirred at room temperature for 20 minutes and allowed to stand for 15 hours. Then, excess triethylamine and acetone are distilled off under reduced pressure. To the resulting residue is added 50 ml of water, and the solution is extracted three times with ethyl acetate. The ethyl acetate extract layer is washed with sodium bicarbonate saturated aqueous solution, water and sodium chloride saturated water in this sequence, dried and blown into by hydrochloric acid gas. Excess hydrochloric acid gas and ethyl acetate are distilled off under reduced pressure. To the residue are added 60 ml of ethyl acetate and 30 ml of ether to cause crystallization at 0° C. Deposited crude crystals are recrystallized from a mixed solvent of ethyl acetate/isopropanol (100/7) to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxamide hydrochloride, m.p. 145°-150° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.O.[NH2:14][NH2:15]>CC(O)C>[C:7]1([C:4]2[S:3][C:2]([NH:14][NH2:15])=[N:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNc1nnc(-c2ccccc2)s1

Procedure:
A solution of the 2-Chloro-5-phenyl-[1,3,4]thiadiazole (2 mmol) and hydrazine hydrate (6 mmol, 3 eq) in iPrOH (10 mL) was heated at reflux overnight. The solvent was evaporated, water was added, and the product was isolated by filtration (110 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6]N=[C:4]([CH3:8])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+:19].[NH4+].[CH3:21][OH:22]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[N:19]=[C:6]([CH2:21][OH:22])[CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: [NH4+]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: Cc1cc(Br)cc(CO)n1

Procedure:
To a solution of 4-bromo-2-methyl-pyridine (5.70 g, 32.14 mmol) in methanol (100 mL), H2SO4 (0.3 mL) is added. The mixture is heated to reflux before a solution of ammonium peroxydisulfate (7.33 g, 32.14 mmol) in water (53 mL) is carefully added. The mixture is stirred at reflux für 2 h before two more portions of ammonium peroxydisulfate (2×7.33 g) is added as a sat. aq. solution. Stirring is continued at reflux for 3 h. Methanol is removed under reduced pressure and the remaining solution is diluted with sat. aq. NaHCO3 solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:7 to give (4-bromo-6-methyl-pyridin-2-yl)-methanol (1.31 g) as pale yellow solid; LC-MS: tR=0.31 min; [M+1]+=201.96; 1H NMR (CDCl3): δ 2.55 (s, 3H), 3.59 (s br, 1H), 4.72 (s br, 2H), 7.28 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](=O)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Br)(Br)([Br:21])=O.C(=O)(O)[O-].[Na+].O>ClCCl>[Br:21][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrle (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed, The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: C1=COCCC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OC2CCCCO2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 45.23 mmol) in CH2Cl2 (100 mL). To this was added 3,4-dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added p-toluenesulfonic acid (389 mg, 2.26 mmol) and the resulting solution was allowed to react, with stirring, for 10 minutes while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The reaction mixture was then quenched by the adding 100 mL of NaHCO3. The resulting mixture was washed with 100 mL of NaHCO3 and 100 mL of brine. The mixture was dried over MgSO4 and concentrated under vacuum using a rotary evaporator. This resulted in 15 g (98%) of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate as yellow oil.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.CN(C)C(=O)C.Cl[S:43]([NH2:46])(=[O:45])=[O:44].Cl.C(=O)([O-])[O-].[Na+].[Na+].O>>[S:43](=[O:45])(=[O:44])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:46]
Reactant: NS(=O)(=O)Cl
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (16) (11.5 g, 0.0221 mol) in N,N-dimethylacetamide (160 mL, 1.7 mol) was added chlorosulfonamide (6.64 g, 0.0575 mol), and the reaction stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C., at which point 12 M hydrochloric acid (90 mL, 1.1 mol) was added dropwise via an addition funnel over 25 min, keeping the internal reaction temp below 50° C. Once the addition was complete, the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was next quenched carefully via slow addition of a suspension of sodium carbonate (70.30 g, 0.6633 mol) in water (200.0 mL, 11.10 mol). The resulting suspension was filtered and the solids were rinsed with EtOAc (3 rinses, total—800 mL). The solids were set aside, and the filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted 3×EtOAc (total EtOAc—2000 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via column chromatography (applied with CH2Cl2, 400 g column, eluent 0-10% MeOH:CH2Cl2 over 80 min then 10% MeOH: CH2Cl2 for 20 min) to afford {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (10.3 g, 96%). LCMS: (FA) ES+ 485; 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.25 (s, 1H), 7.22-7.13 (m, 2H), 5.98 (s, 1H), 5.52 (d, J=32.8, 1H), 5.34 (s, 1H), 4.43-4.35 (m, 1H), 4.32 (dd, J=7.5, 9.8, 1H), 4.22 (td, J=2.5, 5.0, 1H), 4.16 (dd, J=7.3, 9.8, 1H), 3.34 (s, 4H), 3.10 (dd, J=2.1, 16.6, 1H), 3.02 (dd, J=4.8, 16.6, 1H), 2.58-2.46 (m, 1H), 2.28 (ddd, J=2.2, 6.9, 14.8, 1H), 2.12-1.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(F)c(OC[C@@H](O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (13.0 g) was dissolved in 130 mL of anhydrous NMP:diglyme (1:9) solution under nitrogen and heated to 150° C. A suspension of sodium hydride (1.2 g of 60% NaH in mineral oil) in 26 mL of anhydrous NMP:diglyme (1:9) was added all at once via cannula while stirring. After 15 minutes, the reaction was removed from heating, cooled 5 minutes, and then poured into a mixture of ice, 0.5 L EtOAc, and 0.25 L 1 N HCl. The layers were separated and the organic layer was washed with water and brine, and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 8.2 g of partially purified solid which was then purified by silica gel column (1:1 DCM:hex to DCM). 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 7.18-7.28 (m, 3H), 6.95-7.06 (m, 4H) 5.16 (m, 1H), 5.04 (s, 2H), 4.42 (m, 1H), 4.02 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=[CH:28][CH:27]=1.Cl>C(O)(C)C>[O:34]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:25][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:31]=2[CH:32]=[CH:33]1
Reactant: Nc1cccc2occc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4occc34)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 85 °C
Yield: 109.8 %

Procedure:
A mixture of 4chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (0.1 g), 4-aminobenzofuran (0.057 g), isopropanol (4 ml) and a solution of hydrogen chloride in isopropanol (6M, 0.06 ml) was stirred and heated to 85° C. for 3 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed in turn with a 1:1 mixture of diethyl ether and isopropanol and with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.14 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.9 (s, 3H), 3.3-4.0 (broad m, 10H), 4.05 (s, 3H), 4.35 (m, 2H), 6.9 (s, 1H), 7.4 (m, 2H), 7.45 (t, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.3 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1C(O)=O)=[N+:15]=[N-:16].C(Cl)CCl.CCN(C(C)C)C(C)C.C1C[O:42][CH2:41]C1>CN(C1C=CN=CC=1)C>[N:14]([C:17]1[CH:18]=[CH:22][C:23]([C:41]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]=3[CH2:7][CH2:8]2)=[O:42])=[CH:24][CH:25]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)CCNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C(=O)c1ccc(N=[N+]=[N-])cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 equivalent) was dissolved in THF (0.1 M) along with azidobenzoic acid (1.5 equivalents), EDC (1.5 equivalents), DMAP (0.18 equivalents), and DIEA (1.5 equivalents). The reaction was stirred at room temperature overnight. The reaction was then washed with 10% citric acid, saturated sodium carbonate, and brine. The organic layer was then dried over sodium sulfate and the organic solvent removed under reduced pressure. The material was then purified via flash chromatography using 8% acetone/1% ammonia solution/petroleum spirit running solvent to give the title compound. (MH+) 323.2.
Reaction SMILES: O[C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C)(=O)C>[Pd].C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17]2.[CH3:20][O:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[CH:9][CH:10]=2)[CH:15]=1
Reactant: CCOC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C)c1ccc2cc(OC)ccc2c1
Product: COc1ccc2ccccc2c1

Procedure:
Ethyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (7,5 g, 27,3 mmol), acetic anhydride (6,14 g, 60,2 mmol), toluene (37 ml) and palladium catalyst (5% on carbon, 0,75 g) were heated (140° C.) under a hydrogen atmosphere (10 bar) for 14 hours. Ethyl 2-(6-methoxynaphth-2-yl)propionate was formed with a selectivity of 92% at a 2-methoxynaphthalene conversion of 60%.