Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cn1

Procedure:
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]1([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N+:18]([O-])=[CH:17][CH:16]=[CH:15]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:29]1([C:35]2[C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:43][C:42]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[N+:36]=2[O-])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:3][C:17]1[N:18]=[C:19]2[C:14]([CH:13]=[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20]2)=[CH:15][CH:16]=1.[Cl:3][C:41]1[CH:40]=[CH:39][N:38]=[C:37]2[C:42]=1[CH:43]=[C:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:36]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1c(-c2ccccc2)c(-c2ccccc2)cc2cccnc21
Reactant: [O-][n+]1cccc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Product: Clc1ccnc2nc(-c3ccccc3)c(-c3ccccc3)cc12
Temperature: 25 °C

Procedure:
POCl3 (10 ml, 107 mmol) was added dropwise to a mixture of 6,7-diphenyl-1,8-naphthyridine 1-oxide and 2,3-diphenyl-1,8-naphthyridine 1-oxide (Intermediates C) (3 g, 10.06 mmol) at 0° C. The reaction mixture was allowed to warm at room temperature and heated at 100° C. for 2 h. The mixture was poured carefully onto ice/water and the pH was adjusted to pH 8-9 by addition of Na2CO3 (solid) portionwise. The aqueous layer was separated and extracted with DCM (3×150 ml). The organic portions were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. Purification of the crude oil by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded 7-chloro-2,3-diphenyl-1,8-naphthyridine and 5-chloro-2,3-diphenyl-1,8-naphthyridine:
Reaction SMILES: O[C:2]1([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:9]2[C:4]([C:5]([CH3:12])=[CH:6][CH:7]=[C:8]2[CH3:11])=[N:3]1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].C1C[O:30]CC1>>[C:23]([O:25][N:3]1[C:4]2[C:9](=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12])[CH:10]=[C:2]1[C:13]([O:15][CH3:16])=[O:14])(=[O:30])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1(O)C=c2c(C)ccc(C)c2=N1
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1cc2c(C)ccc(C)c2n1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 0.3 g (1.37 mmol) of methyl 2-hydroxy-4,7-dimethylindole-2-carboxylate and 0.13 ml of pyridine in 20 ml of anhydrous THF was cooled, to 0° C. and 0.12 ml of acetyl chloride was gradually added dropwise. The reaction mixture was stirred for 1 hour and then added dropwise to ice water. The crystals were separated by filtration and dried under reduced pressure to provide 0.30 g of green crystals. Yield: 92%
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:1])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Bromine (4.25 ml; 85 mmol) in AcOH:CHCl3 (1:1; 10 ml) was added to a vigorously stirred solution of the compound of example 20b (25.92 g; 80 mmol) in AcOH:CHCl3 (1:1; 110 ml) at 55-60° C. for 15 min. The mixture was stirred at room temperature for 5 min. and poured over crushed ice and NaHCO3 and extracted with EtOAc. The EtOAc layer was washed with water, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 19.34 g, (60%); mp, 84-85° C. (EtOAc-PE 60-80° C.); analysis: C16H19O7Br: requires C, 47.66; H, 4.75; Br, 19.82. found: C, 48.08; H, 4.82; Br, 19.40%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[OH-].[K+].[C:16](=S)=[S:17].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23]Cl>C(O)C.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:16]([S:17][CH2:23][C:22]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]([F:19])[CH:21]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Reactant: S=C=S
Reactant: COc1ccc(CCl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-5-carbohydrazide (356 mg, 2.00 mmol) and potassium hydroxide (85%, 198 mg, 3.00 mmol) in ethanol (15 mL) was added carbon disulfide (0.180 mL, 3.00 mmol), and the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, a mixture of the obtained residue and N,N-dimethylformamide (10 mL) was tightly sealed in a vial, and the microwave was irradiated at 150° C. for 30 sec. After cooling to room temperature, 3-fluoro-4-methoxybenzyl chloride (698 mg, 4.00 mmol) was added, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate to give the title compound (478 mg, yield 67%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].N1C(C)=CC=CC=1C.[Na]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:28]3[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Temperature: 156.5 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol) described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7 mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated and stirred at 155-158° C. for 2 hours. After returning the reaction system to room temperature, it was dissolved in tetrahydrofuran, saturated sodium bicarnobate water was added and stirred therewith for 10 minutes, the mixture was concentrated under reduced pressure, the precipitated solid was filtered out and subjected to silica gel column chromatography (Fuji Silysia NH Type, eluent—hexane:ethyl acetate=50:50→ethyl acetate alone), the fraction containing the target substance was concentrated and the obtained solid was washed with diethyl ether. It was then dried under reduced pressure to obtain the title compound (1.84 g, 4.63 mmol, 52.6%).
Reaction SMILES: [CH2:1]([N:7]([CH3:19])[C:8]([C:10]1[O:11][C:12]([C:15](=O)[CH2:16][Br:17])=[CH:13][CH:14]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:20]([NH:23][C:24]([NH2:26])=[S:25])(=[NH:22])[NH2:21]>CC(C)=O>[BrH:17].[NH:23]([C:24]1[S:25][CH:16]=[C:15]([C:12]2[O:11][C:10]([C:8](=[O:9])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:19])=[CH:14][CH:13]=2)[N:26]=1)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NC(N)=S
Reactant: CCCCCCN(C)C(=O)c1ccc(C(=O)CBr)o1
Solvent: CC(C)=O
Product: Br
Product: CCCCCCN(C)C(=O)c1ccc(-c2csc(NC(=N)N)n2)o1

Procedure:
A mixture of 6.8 g. (0.02 mole) of N-n-hexyl-N- methyl-5-(2-bromoacetyl)furan-2-carboxamide, 2.4 g. (0.02 mole) of guanylthiourea and 225 ml. of acetone was stirred at room temperature for 2 hours. The solid was recovered by filtration (5.4 g.) and recrystallized from ethanol to give 812 mg. of the title compound as a white solid, mp. 226°-228° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH:36]1([CH2:41][C:42](Cl)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][C:42]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(Cl)CC1CCCC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CCCC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and cyclopentylacetyl chloride (Lancaster, Cat. No. L14562). LCMS (M+H)+: m/z=595.2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24]([C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36](=[O:47])[NH:37][CH2:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=5)[CH:33]=[CH:32][C:31]=4[F:48])=[O:28])=[CH:25][N:26]=[C:20]3[CH:19]=2)=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1.CO.C(OCC)C>[ClH:11].[F:46][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][C:42]=1[F:45])[CH2:38][NH:37][C:36]([C:34]1[CH:33]=[CH:32][C:31]([F:48])=[C:30]([NH:29][C:27]([C:24]2[N:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:16]=[N:17][C:12]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:13][CH:14]=4)=[CH:19][C:20]3=[N:26][CH:25]=2)=[O:28])[CH:35]=1)=[O:47]
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(Cl)nc4)ccn23)c1
Reactant: OCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(OCCN5CCCC5)nc4)ccn23)c1
Temperature: 60 °C

Procedure:
A solution of 2-(pyrrolidin-1-yl)ethanol (30.5 mg, 0.265 mmol) and sodium hydride (6.36 mg, 0.265 mmol) in toluene (442 μl) was stirred at RT for 30 mins and treated with 7-(6-chloropyridin-3-yl)-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1). The reaction mixture was heated at 60° C. for 1 hour and the reaction was quenched with wet MeOH. Purification of the mixture by chromatography on silica eluting with 0-20% (2M NH3 in MeOH)/DCM afforded a yellow solid. The solid was dissolved in MeOH and treated with 2M HCl in diethyl ether (1 eq). The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 2M NH3 in MeOH/TBME afforded a solid. The solid was treated again with 2M HCl in diethyl ether and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:28]([NH2:35])[C@H:27]1[OH:36].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.153 g, 0.43 mmol), (1R,2S)-(+)-cis-1-amino-2-indanol (0.065 g, 0.43 mmol), sodium cyanoborohydride (0.041 g, 0.65 mmol), and acetic acid (3 drops) were combined in CH2Cl2 (1.5 mL), and the reaction was stirred for 30 minutes at room temperature. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ncccc1F
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ncccc2F)nc2nc(N)sc12
Yield: 38.8 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (348 mg, 1.16 mmol) and 2-((R)-1-chloroethyl)-3-fluoro-pyridine (240 mg, 1.5 mmol). Purification by flash column chromatography (eluent DCM:methanol gradient) resulted in 190 mg (47% yield) of the title compound with a diastereomeric excess of 60%. Of this material 55 mg was further purified by preparative HPLC. The last eluting isomer was collected to yield 21 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][CH:16]([NH2:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH:16]([CH3:17])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 865 mg, 3.15 mmol) and propan-2-amine (3.725 g, 63.0 mmol) in DMF (3 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated product was filtered, washed with water and dried in vacuo to obtain the title compound as a white solid (893 mg, 95% yield). HPLC (condition B): retention time=3.28 min. LCMS MH+ m/z 297.00. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (1 H, s), 7.86 (1 H, d, J=1.76 Hz), 7.02 (1 H, d, J=1.76 Hz), 4.24-4.53 (1 H, m), 1.29 (6 H, d, J=6.16 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)nc1Br
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(Br)n3)nc2c1
Temperature: 120 °C
Yield: 269.8 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (1.23 g, 6.25 mmol) in N,N-dimethylacetamide (100 mL) was added 6-bromo-5-methoxypicolinaldehyde (1.35 g, 1.2 mmol) followed by NaHSO3 (0.98 g, 9.38 mmol) and p-toluenesulfonic acid monohydrate (1.19 g, 6.25 mmol). The resulting mixture was heated at 120° C. for 20 h. After that time the reaction was cooled to it, concentrated under reduced pressure and diluted with saturated Na2CO3. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) followed by trituration with ethyl acetate to give 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.27 g, 52%) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 11.03 (br s, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=3)=[CH:9][C:8]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:7]=3[C:6]=2[CH2:5]1.[CH3:31]I.O>CN(C)C=O>[CH3:31][N:28]1[C:7]2[C:6]3[CH2:5][N:4]([CH3:3])[CH2:13][CH2:12][C:11]=3[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:22])[CH3:23])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[C:26](=[O:30])[C:27]1=[O:29]
Reactant: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)NC(=O)C3=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)N(C)C(=O)C3=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
NaH 60% (110 mg, 2.8 mmol) was added at 0° C. to a mixture of 8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1-H-pyrrolo[3,2-h]isoquinoline-2,3-dione (1 g, 2.5 mmol) in dimethylformamide (10 ml). The mixture was stirred at 0° C. for 10 min. Methyliodide (175 μl, 2.8 mmol) was added and the mixture was stirred for one hour at ambient temperature. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×25 ml). The organic phase was dried over sodium sulphate and evaporated. Pure 1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione was obtained after purification on silica gel using dichloromethane/acetone/methanol (8:1:1) as the eluent. Yield 160 mg, m.p. 232-240° C. (decomposes).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[OH:25])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:27]1[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=1.[I-].[Na+]>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH:12]2[O:25][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[N:32]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)C1
Reactant: COC(=O)c1cccc(Cl)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC2CN(C(=O)OC(C)(C)C)CCOC2c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 53 mg) was added to a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (400 mg) in DMF (5 mL). After stirring at room temperature for 20 min, methyl 6-chloropicolinate (280 mg) and sodium iodide (330 mg) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (207 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C1([C:31]2[CH:35]=[CH:34][C:33](=[CH2:36])[C:32]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C=CC=CC=1>O1CCCC1.O>[CH:31]1([C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:3]2[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:24]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:35]=[CH:34][CH:33]=[CH:36]1
Reactant: CCCCCC
Reactant: C=C1C=CC(c2ccccc2)=C1c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(C(c2ccccc2)(c2ccccc2)C2c3ccccc3-c3ccccc32)C=C1
Reaction time: 0.67 h
Yield: 42 %

Procedure:
12.3 cm3 (30.7 mmol) of a 2.5 molar hexane solution of n-butyllithium were slowly added to a solution of 5.10 g (30.7 mmol) of fluorene in 60 cm3 of tetrahydrofuran at room temperature. After 40 minutes, 7.07 g (30.7 mmol) of diphenylfulvene were added to the orange solution and the mixture was stirred overnight. 60 cm3 of water were added to the dark red solution, whereupon the solution became yellow-colored, and the mixture was extracted with ether. The ether phase was dried over MgSO4 and concentrated and the residue was left to crystallize at -35° C. 5.1 g (42%) of 1-cyclopentadienyl-1-(9-fluorenyl)-diphenylmethane were obtained as a beige powder. 1.25 g (3.15 mmol) of 1-cyclopentadienyl-1-(9-fluorenyl)-diphenylmethane were reacted with 6.3 mmol of butyllithium analogously to Example 1. The dilithium salt was reacted with 1.0 g (3.15 mmol) of HfCl4 analogously to Example 1. Filtration of the orange reaction mixture over a G4 frit and extraction of the filtrate with 100 cm3 of toluene gave 0.70 g (34%) of the hafnocene dichloride complex as a yellow-orange powder. Correct elemental analysis. The mass spectrum gave M+ =644.
Reaction SMILES: CN.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C[CH2:28][N:29]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.O>[CH3:28][NH:29][C:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]2([CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)[CH:16]=1)=[O:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.8 %

Procedure:
A solution of methylamine in THF (2 mL) was added to a stirred solution of 1′-(tert-butyoxycarbonyl)spiro[indene-1,4′-piperidine]-3-carboxylic acid (C4) (0.51 g, 1.55 mmol), EDAC HCl (0.6 g, 3.00 mmol), HOBt (0.31 g ) in DMF (10 mL), and the solution was stirred at room temperature for 12 h. The solution was poured into water (50 mL), the aqueous layer was extracted with EtOAc (3×50 mL), dried, and concentrated under reduced pressure. The crude product was purified by Biotage SP1 on silica gel eluting with 12-100% EtOAc in hexanes to provide tert-butyl 3-(methylcarbamoyl)spiro[indene-1,4′-piperidine]-1′-carboxylate (C5) as a white solid (0.45 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 343 (M+1), Rt 3.0 minutes. 1HNMR (500 mHz, CDCl3) δ 7.73 (d, 1H), 7.23 (m, 3H), 7.14 (s, 1H), 6.05 (brm, 1H), 4.11 (m, 2H), 3.03 (m, 2H), 2.93 (d, 3H), 1.95 (m, 2H), 1.44 (s, 9H), 1.30 (m, 2H).