Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([NH2:11])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=O)[C:16](OC)=[C:15]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[OH:13][C:14]1[C:15]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:16]2[C:17]([N:12]=[C:4]3[C:5](=[N:11]2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]3[O:2][CH3:1])=[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=12
Reactant: COc1ccc(OC)c(N)c1N
Reactant: CCOC(=O)C1=C(OC)C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3c(OC)ccc(OC)c3nc12
Yield: 92.6 %

Procedure:
In 50 ml of hot ethanol was dissolved 1.68 g of 3,6-dimethoxy-o-phenylenediamine. To this solution was gradually added 2.6 g of ethyl 1,4-dihydro-1,4-dioxo-3-methoxy-2-naphthoate under heating with stirring, and the mixture was refluxed for a further 2 hours. The reaction mixture was cooled and the precipitated solid was collected by filtration and recrystallized from benzene to give 3.50 g (92.6% yield) of ethyl 5-hydroxy-8,11-dimethoxybenzo[a]-phenazine-6-carboxylate as red needles, m.p. 290° C. (decomp.), Anal. Calcd.: (%) for C21H18N2O5 ; C, 66.66; H, 4.80; N, 7.40; Found: C, 66.46; H, 4.56; N, 7.53
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:9])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH:3]([OH:9])[CH2:4][S:5]([OH:8])(=[O:7])=[O:6]
Reactant: O=S(=O)([O-])CC(O)CCl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(O)CC(O)CCl
Reaction time: 4 h

Procedure:
The sodium 3-chloro-2-hydroxypropanesulfonate reactant is added to the mixture, and the etherification reaction is conducted at 40° C over a period of 4 hours. The reaction mixture is neutralized to a pH of 8.3 with acetic acid, then filtered, washed twice with 50% isopropanol and once with 100% isopropanol. The galactomannan ether product is recovered and air-dried.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[Br:32]Br>ClCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:32])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: BrBr
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 134.3 %

Procedure:
5-Acetyl-8-benzyloxy-1H-quinolin-2-one (Preparation 6) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45° C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45° C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([C:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH:22]=[O:23])[CH:3]=1)=[O:21])([CH3:18])[CH3:17])#[N:20]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(N)c2)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the above-mentioned crude product of N-(3-aminophenyl)-3-(1-cyano-1-methylethyl)benzamide in tetrahydrofuran (15 mL) was added a mixture of formic acid (1 mL) and acetic anhydride (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (407 mg, 83%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[NH2:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Yield: 27.4 %

Procedure:
In a similar fashion using route 6 general procedure 14, N-(5-chloroquinolin-8-yl)-4-methyl-2-nitrobenzenesulfonamide (Intermediate 155) (160 mg, 0.42 mmol), Raney nickel (32 mg, 20% wt), hydrazine hydrate (63 mg, 1.27 mmol) and MeOH (10 ml) gave the title compound (40 mg, 27%) after purification by column chromatography with DCM as the eluent followed by recrystallisation from DCM/n-pentane.
Reaction SMILES: [ClH:1].[CH2:2]([C@@H:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:7]1)[CH2:3][CH2:4][CH3:5].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[ClH:1].[ClH:1].[CH2:2]([C@H:6]1[CH2:7][N:8]([C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:9][CH2:10][N:11]1[CH2:30][C:26]1[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1cccnc1
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1Cc1cccnc1

Procedure:
3(S)-Butyl-1-(1-naphthoyl)piperazine hydrochloride (0.200 g, 0.601 mmol) was reacted with pyridine-3-carboxaldehyde (0.062 mL, 0.661 mmol), sodium triacetoxyborohydride (0.321 g, 1.52 mmol), in dichloroethane (7 mL) at pH 5-6 in the presence of crushed molecular sieves as described in Example 8, Step A. The crude product was purified by silica gel chromatography with 30% acetone in hexane, followed by preparative HPLC (80-75% solvent A). After ion exchange, the title compound was isolated. FAB ms (m+1) 388. Anal. Calc. for C25H29N3O.2.3 HCl.0.95 H2O. C, 61.49; H, 6.85; N, 8.60. Found: C, 61.49; H, 7.01; N, 8.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[N:25]=1.C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[Br:23][C:24]1[N:25]=[C:26]([CH2:30][N:11]2[C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]3[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=3)=[CH:10]2)[CH:27]=[CH:28][CH:29]=1
Reactant: BrCc1cccc(Br)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Yield: 16.9 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 2 using 75 mg (0.255 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 76.8 mg (0.306 mmol) of 2-bromo-6-bromomethyl-pyridine, 0.61 mL (0.306 mmol, 0.5 M in toluene) of potassium hexamethyldisilazane, and 2.5 mL of THF. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 20 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C23H18BrN3O3 [M+H]: 464.05 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.0 min.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1>CO.O>[NH2:14][C:10]1[N:11]=[CH:12][N:13]=[C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)[CH:9]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OC1CNC1
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(N2CC(O)C2)ncn1
Yield: 84.6 %

Procedure:
A solution of 3-azetidinol hydrochloride (454 mg, 4.1 mmol) in MeOH and water was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure. The resultant residue was then added to a solution of 6-chloro-pyrimidin-4-ylamine (151 mg, 1.16 mmol) in IMS (10 mL) under argon and heated under reflux for 18 hours. The reaction mixture was cooled and then loaded onto an Isolute® SCX-2 column. The column was then washed with MeOH and eluted with 2 M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure and the resulting residue was purified by flash chromatography (NH2 cartridge, 0-5% MeOH in DCM) to give the desired compound as a white solid (163 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J=1.0 Hz, 1H), 6.18 (s, 2H), 5.65 (d, J=6.5 Hz, 1H), 5.21 (d, J=1.1 Hz, 1H), 4.54-4.53 (m, 1H), 4.07 (dd, J=8.7, 6.7 Hz, 2H), 3.59 (dd, J=8.8, 4.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]([NH:21][CH2:22][CH2:23]CCCCN)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:29]1(N)C(F)=C(F)C(F)=[C:31]([NH2:38])[C:30]=1F.[ClH:41].Cl>>[ClH:41].[ClH:41].[NH2:38][CH2:31][CH2:30][CH2:29][CH2:23][CH2:22][NH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(NCCCCCCN)CC[C@@H]12
Agent: Cl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCCCN)CC[C@@H]12

Procedure:
N-(3-methoxy-1,3,5(10)-estratrien-17-yl)-1,6-hexanediamine and the corresponding dihydrochloride salt;
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH:38]1([S:41]([NH:44][C:45](=O)[O:46]CC)(=[O:43])=[O:42])[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O.O>[CH:38]1([S:41]([NH:44][C:45](=[O:46])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: CCOC(=O)NS(=O)(=O)C1CC1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 20.3 %

Procedure:
To a solution of the amine 126 (500 mg, 0.953 mmol) in DME (4 ml) was added the carbamate 374 (460 mg, 2.5 eq, 2.383 mmol) and the reaction mixture was heated to 120° C. for 1 day. The mixture was cooled to RT, diluted with EtOAc and water and the organic phase was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc to 50% Acetone in EtOAc) afforded 375 as a brown oil (130 mg, 55%). MS (m/z)=672.5 (M+H)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1>C(Cl)(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(N)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (0.50 g, 4.9 mmol) and chloroacetyl chloride (0.56 g, 4.9 mmol) were added dropwise at 0° C. to a stirred suspension of 5-Amino-2-cyanopyridine (0.27 g, 2.25 mmol) in chloroform (10 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with chloroform (50 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and the crude product obtained was crystallized from chloroform:petroleum ether (1:2) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:17]=3[CH2:16][CH2:15][NH:14][C:13]4=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(Br)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-1,3-dihydro-indol-2-one (42.4 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([CH:19]1[NH:23][C:22](=[O:24])[CH2:21][NH:20]1)([CH3:18])[CH3:17].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:20]1[CH2:21][C:22](=[O:24])[NH:23][CH:19]1[CH:16]([CH3:18])[CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)C1NCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C1NC(=O)CN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Into an ice-cold solution of N-(benzyloxycarbonyl) glycine (26 g) and 2-isopropyl-4-imidazolidinone (16 g) in THF (260 ml), a solution of DCC (25.4 g) in THF (100 ml) was added dropwise. After stirring for 2 hours at 20° C., the precipitate was filtered off and the filtrate was evaporated to dryness. Crystallization of the residue from 2-propanol yielded 33.5 g of the title compound, m.p. 137°-139° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].C(#N)C.[CH2:16]([O:18]CC)[CH3:17]>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:16]([CH3:17])=[O:18]
Reactant: CCOCC
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: CC#N
Product: CC(=O)Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 960 mg of n-butyllithium in diethyl ether was added dropwise 1480 μl of α-picoline at 0° C. under an argon and the reaction mixture was stirred for 10 minutes at 0° C. To the reaction mixture was added 782 l of acetonitrile and the mixture was stirred for 3 hours at room temperature, followed by extraction with 30 ml of 1.5N-sulfuric acid. The acidic solution was washed with 25 ml of diethyl ether, and made alkaline with a 2N-aqueous sodium hydroxide solution and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residual oil was distilled under reduced pressure to give 700 mg of methyl 2-pyridylmethyl ketone as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:32])=[CH:17][N:18]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[C:26]1([S:23]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[C:16]([Br:32])=[CH:17]2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(N3CCNCC3)cccc21
Yield: 97.5 %

Procedure:
To a suspension of 0.102 g (0.2 mmole) 4-(1-benzenesulfonyl-3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 3 mL ethanol was added 2 mL concentrated hydrochloric acid. The mixture was heated under reflux until all solid has dissolved. The mixture was concentrated to dryness under reduced pressure and the residue was recrystallized from methanol/ether to provide 0.082 g of 1-benzenesulfonyl-3-bromo-4-piperazin-1-yl-1H-indole (31), mp 304-305° C., as hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 91.3 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 4-methylbenzoyl chloride, 14.6 mg (91%) of the title compound were recovered as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1)=[O:31]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:15])[CH:9]([CH3:14])[CH2:10]2)[CH2:33]1)=[O:31]
Reactant: C[C@H]1CNCC[C@]1(O)c1ccc(F)cc1
Reactant: O=C1CCN(C(=O)CNc2ncnc3cc(Cl)c(Cl)cc23)C1
Product: CC1CN(C2CCN(C(=O)CNc3ncnc4cc(Cl)c(Cl)cc34)C2)CCC1(O)c1ccc(F)cc1

Procedure:
2-(6,7-dichloroquinazolin-4-ylamino)-1-(3-(4-(4-fluorophenyl)-4-hydroxy-3-methylpiperidin-1-yl)pyrrolidin-1-yl)ethanone was prepared as a mixture of 4 isomers from (3S,4R)-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (prepared via general procedure O, AA) and 1-(2-(6,7-Dichloroquinazolin-4-ylamino)acetyl)pyrrolidin-3-one (Preparation #32) according to general procedure E then purified via chiral preparative NP-HPLC (isocratic 2.5% methanol:2.5% ethanol:95% heptane:0.1% diethylamine modifier at 16 mL/min, room temperature; UV detection monitored at 265 nm; Daicel AD-H column, 20×250 mm, 5 um particle) to yield two products. Product A eluted at Rt 7.5-11 min. Product B eluted at Rt 11-15 min. Product A has a positive optical rotation and product B has a negative optical rotation. Product A was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 1 eluted at Rt 14-16.3 min. Isomer 2 eluted at Rt 16.3-19 min. Both isomers have positive optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 1 & 2: RP-HPLC (Table 1, Method a) Rt 1.99 min; m/z: (M+H)+ 532. Product B was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 3 eluted at Rt 13.3-16 min. Isomer 4 eluted at Rt 16.3-19 min. Both isomers have negative optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 3 & 4: RP-HPLC (Table 1, Method a) Rt 1.92 min; m/z: (M+H)+ 532.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]([O:15][C:16](Cl)(Cl)Cl)=[O:14]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13](=[O:14])[O:15][C:16]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Oc1ccc(F)cc1Cl)Oc1ccc(F)cc1Cl
Reaction time: 6 h
Yield: 73.5 %

Procedure:
2-Chloro-4-fluorophenol (4.4 kg, 30 mol), triethylbenzylammonium chloride (17.1 g) and methylene chloride (7 liters) were put in a 20-liter three-neck flask as equipped with a stirrer and a dropping funnel, and cooled in an ice-water bath. 5N sodium hydroxide aqueous solution (6 liters) was gradually added thereto with stirring vigorously. Next, trichloromethyl chloroformate (885 ml, 7.35 mol) was gradually dropwise added thereto over a period of about 6 hours. After addition, the reaction liquid was stirred overnight. After reaction, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (1000 ml×2). The organic layers were combined, washed with 1N sodium hydroxide aqueous solution (4 liters) and water (5 liters) and then dried with anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed from the organic layer by distillation under reduced pressure to obtain a white solid of bis(2-chloro-4-fluorophenyl)carbonate (4.9 kg, 5.4 mol). Yield: 100%. Spectral data and other data of the product are those as shown in Example 2.
Reaction SMILES: [H-].[Na+].CC(C)([O-])C.[K+].Cl[CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:18][CH2:19][C:20]#[N:21])[CH2:12]1.O>CN(C=O)C>[C:20]([CH:19]1[CH2:18][N:13]2[CH2:12][CH:11]([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10]1)#[N:21]
Reactant: N#CCCN1CCCCC(CCl)C1
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1CC2CCCCN(C1)C2
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a stirred suspension of sodium hydride (1.5 g, 80%) and potassium t-butoxide (0.5 g) in DMF (100 ml) was added 3-chloromethyl-1-(2'-cyanoethyl)homopiperidine (D6) (5 g) and the reaction mixture was carefully warmed to 70° C. for 1 hour. On cooling, water (5 ml) was carefully added and the DMF was removed by rotary evaporation. Extraction of the residue with ethyl acetate, concentration and distillation afforded the (±) 8-cyano-1-azabicyclo-[4,3,1]-decane (D7) (4.0 g, 90%) bp 68°-73°/0.1 mm.